Dieter Kabelitz - Academia.edu (original) (raw)

Papers by Dieter Kabelitz

Cells, Nov 30, 2020

Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but o... more Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but occur at increased frequency in mucosal tissues. The discovery of a second T-cell receptor 35 years ago was certainly unexpected [1-4]. Looking back, however, it is obvious that the scientific interest in γδ T-cell research has been undulating since then. A breakthrough of γδ T-cell research was the discovery that the major population of human γδ T cells does not recognize peptides presented by Human Leukocyte Antigen (HLA) molecules (like the conventional CD4 + or CD8 + T cells carrying the αβ T-cell receptor) but rather recognize nonpeptidic phosphorylated molecules secreted by bacteria [5]. Such "phosphoantigens" have been discovered not only in many bacteria and some parasites but also in eukaryotic cells as intermediates of the mevalonate pathway of cholesterol synthesis [6]. Overproduction of phosphoantigens in tumor cells due to a dysregulated mevalonate pathway has been shown to activate tumor-reactive γδ T cells [7]. How such phosphoantigens are recognized by γδ T cells has been a mystery for many years. A landmark paper by Harly and colleagues identified an indispensable role of the butyrophilin family transmembrane molecules, specifically butyrophilin (BTN) 3A1 [8]. Exciting new studies have recently highlighted a similarly indispensable role of another BTN member, BTN2A1 [9,10]. Other studies have shown that BTN-like molecules are also very important for the regulation of tissue-resident human γδ T cells [11]. Taken together, there has been tremendous recent progress in the elucidation of the molecular pathways of how γδ T cells (as opposed to conventional αβ T cells) are activated and influenced by the local micromilieu. From a translational perspective, the potential advantage of γδ T cells for (cancer) immunotherapy has long been recognized. The more detailed knowledge of how γδ T cells recognize transformed cells independently of HLA restriction has certainly fueled this interest, as reflected by the increasing number of companies devoted to clinical exploration of γδ T-cell immunotherapy [12]. This Special Issue of Cells comprises 17 original papers and review articles on various aspects of γδ T cells in health and disease. In view of the recent and exciting progress in the field, I thought that this would be a wonderful time to collect contributions from leading experts to share their results and amazing new insights with the scientific community. While preparing this Special Issue, we had to mourn the sudden death of Wendy Havran, a giant in the field of γδ T-cell research and an exceptional and close friend to many of us in the γδ T-cell world. I appreciate the support of the publishers to devote this Special Issue to the memory of Professor Wendy Havran. The first paper is an appraisal of Professor Wendy Havran, written by her long-term associate Deborah Witherden. This short editorial illustrates the extraordinary personality of Wendy Havran both as a scientist and as a mentor for a large number of trainees in her lab, many of whom have moved on to take leadership positions at universities or in industry [13]. Four reviews and two original papers in this Special Issue concentrate on characteristics of γδ T cells under physiologic conditions, and how γδ T cells are activated and interact with other immune cells. Fonseca and colleagues present a thorough phenotypic analysis of γδ T cells in a population of 30 Caucasian blood donors with a mean age of 47 years. Even though this is a relatively small cohort,

International Immunology, Jan 24, 2018

It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, ... more It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, perforin and Fas ligand (FasL) in intracellular granules, often referred to as secretory lysosomes. Upon target cell encounter, these organelles are transported to the cytotoxic immunological synapse, where they fuse with the plasma membrane to release the soluble effector molecules and to expose transmembrane proteins including FasL on the cell surface. We previously described two distinct species of secretory vesicles in T and NK cells that differ in size, morphology and protein loading, most strikingly regarding FasL and granzyme B. We now show that the signal requirements for the mobilization of one or the other granule also differ substantially. We report that prestored FasL can be mobilized independent of extracellular Ca 2+ , whereas the surface exposure of lysosome-associated membrane proteins (Lamps; CD107a and CD63) and the release of granzyme B are calcium-dependent. The use of selective inhibitors of actin dynamics unequivocally points to different transport mechanisms for individual vesicles. While inhibitors of actin polymerization/ dynamics inhibit the surface appearance of prestored FasL, they increase the activation-induced mobilization of CD107a, CD63 and granzyme B. In contrast, inhibition of the actin-based motor protein myosin 2a facilitates FasL-, but impairs CD107a-, CD63-and granzyme B mobilization. From our data, we conclude that distinct cytotoxic effector granules are differentially regulated with respect to signaling requirements and transport mechanisms. We suggest that a T cell might 'sense' which effector proteins it needs to mobilize in a given context, thereby increasing efficacy while minimizing collateral damage.

The Journal of Immunology

Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor... more Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor stimulation of resting cells and in the initiation of activation-induced cell death (AICD) of preactivated T cells. CD4-associated p56lck has been implicated not only in the activation of primary T cells, but also in the inhibition of T cell responses. We have previously shown that CD4+ T cell clones can be rescued from AICD when surface CD4 is engaged before the TCR stimulus. In this study, we show that prevention of AICD is associated with a CD4-dependent inhibition of TCR-triggered tyrosine phosphorylation of the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and Vav. We provide evidence for a SLP-76 interaction with Src homology 3 domains of p56lck and identify amino acids 185–194 of SLP-76 as relevant docking site. In view of the multiple functions of p56lck and SLP-76/Vav in the initiation of TCR/CD3/CD4 signaling, we propose a model for the CD4-dependent in...

The Journal of Immunology

The gamma delta TCR is expressed on 1 to 5% of CD3+ human peripheral blood T lymphocytes. The maj... more The gamma delta TCR is expressed on 1 to 5% of CD3+ human peripheral blood T lymphocytes. The majority of peripheral blood gamma delta T cells expresses V gamma 9 paired with V delta 2; this subset strongly responds to certain microbial ligands. Other gamma delta T cell subsets with unknown Ag specificity expressing different V gamma elements are present in peripheral blood and lymphoid tissue. We describe a new anti-human V gamma mAb termed 23D12 with unusual specificity. As revealed by analysis of a large number of T cell clones and transfectants expressing molecularly well-defined gamma delta TCR, mAb 23D12 recognized several, but not all, members of the human V gamma 1 family, specifically V gamma 2, V gamma 3, and V gamma 4 but not V gamma 5 or V gamma 8. In combination with available mAb against V gamma 4, mAb 23D12 was used to identify V gamma 2- or V gamma 3-bearing cells. On average, 23D12+ cells accounted for 18% of peripheral blood gamma delta T cells and 56% of postnatal...

Journal of Leukocyte Biology

Weissmann wrote as early as 1889 that higher organisms contain within themselves the germs of dea... more Weissmann wrote as early as 1889 that higher organisms contain within themselves the germs of death [1]. However, the term, programmed cell death, or apoptosis as it is now known, was defined much later [2]. Thus, it was long recognized that damaged and old cells are eliminated within the body, but the underlying mechanisms are only now beginning to emerge. Apoptosis appears central to the process of negative selection of developing T-cells in the thymus. In regard to organ transplantation, apoptosis contributes to graft rejection and the establishment of graft tolerance. Thus, understanding the regulatory mechanisms of apoptosis may help establish a new protocol for the induction of transplantation tolerance.

Cellular & Molecular Immunology

Oncotarget, 2016

Previously, the expression of a non-secreted IL-4 variant (IL-4δ 13) has been described in associ... more Previously, the expression of a non-secreted IL-4 variant (IL-4δ 13) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ 13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ 13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ 13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.

Cellular & molecular immunology, 2014

Cellular & molecular immunology, 2013

The elusive task of defining the character of γδ T cells has been an evolving process for immunol... more The elusive task of defining the character of γδ T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the α and β T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, γδ T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and αβ T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm γδ T cells excel thanks to their highly empathetic nature. This review gives an overview of...

The Journal of Immunology, 2006

V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the... more V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called “trans-rearrangements.” Such trans-rearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCR proteins on the surface of T cells. Although chimeric receptors are not pathogenic per se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarker for lymphoma risk.

The Journal of experimental medicine, 1991

We have previously reported that peripheral blood gamma/delta + T cells proliferate in high frequ... more We have previously reported that peripheral blood gamma/delta + T cells proliferate in high frequency (1 in 2-20) in response to heat-killed Mycobacterium tuberculosis (M.tb.). In the present study, the T cell receptor phenotype of mycobacteria-responsive human gamma/delta + T cells was analyzed in primary cultures with a set of monoclonal antibodies (mAbs) directed against V gamma 9, V delta 1, and V delta 2. When unseparated T cells were stimulated with M.tb., all proliferating gamma/delta + T cells expressed V gamma 9 (and V delta 2) after culture. Selective depletion of V gamma 9-bearing cells before culture completely abolished the proliferative response of all gamma/delta + cells (but did not inhibit reactivity of alpha/beta + T cells). In addition, when CD4- CD8- thymocytes were stimulated with M.tb., there was again selective outgrowth of V gamma 9+ cells. In this case, the starting responder population contained few (0.5-1.8%) V gamma 9+ and many (11.5-31.5%) V delta 1+ cel...

The Journal of experimental medicine, 1989

It is generally believed that CD2 (T11, sheep erythrocyte receptor) is expressed on all human T c... more It is generally believed that CD2 (T11, sheep erythrocyte receptor) is expressed on all human T cells. In the present study we have identified and characterized a minor subset of CD2- CD3/TCR alpha/beta+ T cells in the peripheral blood of healthy individuals. CD2-CD3+ T cells were enriched in PBMC depleted of plastic-adherent macrophages, E-rosetting (i.e., CD2+) T cells and surface Ig+ B cells. CD2-CD3+ T cells accounted for 0.1-0.8% of PBMC in six individuals. IL-2-dependent long-term clones of CD2-CD3+ T cells neither reacted with a panel of anti-CD2 mAbs nor expressed detectable levels of CD2 mRNA by Northern blot analysis. These clones, however, expressed a full-length TCR C beta mRNA and reacted with mAbs against TCR-alpha/beta, CD3, and CD4, and thus were mature T cells. CD2-CD3/TCR+ T cell clones could be triggered into proliferation, IL-2 production, and cytotoxic effector activity by anti-CD3 and anti-TCR mAbs. We conclude that (a) a minor subset of CD2-, CD3/TCR-alpha/bet...

International Immunology, 2009

Activation of resting T cells in vitro is triggered by combined TCR and CD28 engagement and can b... more Activation of resting T cells in vitro is triggered by combined TCR and CD28 engagement and can be modulated by simultaneous ligation of various other surface receptors. Although the Fas ligand (FasL) is best known for its capacity to initiate cell death in Fas-bearing cells, it has recently been implicated in the regulation of T cell activation. Thus, a cross-talk between the TCR and FasL is likely, but far from being biochemically elucidated. We now report that FasL engagement by immobilized but not soluble FasFc fusion protein and anti-FasL polyclonal antibody blocks the activation of human peripheral T cells even in the presence of CD28 co-stimulation. The data presented here stress the importance of the Fas/FasL system for signal initiation via the TCR-CD3 complex and provide further arguments for a retrograde signaling capacity of FasL or a crucial role of Fas as a co-stimulatory molecule.

Immunology, 1998

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown aetiology. Recently, superan... more Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown aetiology. Recently, superantigens have been implied in the pathogenesis of RA. Superantigens activate a large fraction of T cells leading to the production of cytokines and proliferation. In addition, superantigens direct cellular cytotoxicity towards major histocompatibility complex (MHC) class II‐expressing cells. There is now increasing evidence that cytotoxic T cells may be involved in the pathogenesis of RA. In the inflamed synovia class II‐positive synovial fibroblasts (SFC) are found. In the present study it was tested whether MHC class II‐positive SFC serve as target cells for superantigen‐induced cellular cytotoxicity. SFC were stimulated with interferon‐γ to express class II antigens, then they were cultivated in the presence of CD4‐positive T cells with or without staphylococcal enterotoxins (SE). Cytotoxicity of T cells was measured as release of lactate dehydrogenase from SFC. Specific cytotoxicity wa...

F1000 - Post-publication peer review of the biomedical literature, 2017

Innate T cells are a heterogeneous group of αβ and γδ T cells that respond rapidly (<2 h) upon ac... more Innate T cells are a heterogeneous group of αβ and γδ T cells that respond rapidly (<2 h) upon activation. These innate T cells also share a non MHC class I or II restriction requirement for antigen recognition. Three major populations within the innate T cell group are recognized, namely, invariant NKT cells, mucosal associated invariant T cells, and gamma delta T cells. These cells recognize foreign/self-lipid presented by non-classical MHC molecules, such as CD1d, MR1, and CD1a. They are activated during the early stages of bacterial infection and act as a bridge between the innate and adaptive immune systems. In this review, we focus on the functional properties of these three innate T cell populations and how they are purposed for antimicrobial defense. Furthermore, we address the mechanisms through which their effector functions are targeted for bacterial control and compare this in human and murine systems. Lastly, we speculate on future roles of these cell types in therapeutic settings such as vaccination.

European Journal of Immunology, 2019

F1000 - Post-publication peer review of the biomedical literature, 2017

Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing pri... more Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill-defined. We examined lysis mediated by human Vγ9Vδ2 T effectors in response to the naturally-occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cellpermeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate (POM 2-C-HMBP). CD27+/CD45RA− Th1-like effector cells killed K562 target cells though a mechanism that could be enhanced by either compound or TCR antibody and blocked by Src inhibition or BTN3A1 disruption. Pre-treatment at 4°C decreased HMBPP-induced lysis but did not reduce lysis induced by POM 2-C-HMBP. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 T effectors. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by smallmolecule induction of BTN3A1.

F1000 - Post-publication peer review of the biomedical literature, 2017

γδ T cells are one of the three immune cell types that express antigen receptors. They contribute... more γδ T cells are one of the three immune cell types that express antigen receptors. They contribute to lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. γδ T cells have the capacity of secreting abundant cytokines and exerting potent cytotoxicity against a wide range of cancer cells. γδ T cells exhibit important roles in immune-surveillance and immune defense against tumors and have become attractive effector cells for cancer immunotherapy. γδ T cells mediate anti-tumor therapy mainly by secreting pro-apoptotic molecules and inflammatory cytokines, or through a TCR-dependent pathway. Recently, γδ T cells are making their way into clinical trials. Some clinical trials demonstrated that γδ T cell-based immunotherapy is well tolerated and efficient. Despite the advantages that could be exploited, there are obstacles have to be addressed for the development of γδ T cell immunotherapies. Future direction for immunotherapy using γδ T cells should focus on overcoming the side effects of γδ T cells and exploring better antigens that help stimulating γδ T cell expansion in vitro.

Frontiers in Immunology, 2015

F1000 medicine reports, 2010

γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against... more γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against a variety of tumor cells. Human γδ T cells expressing the Vγ9Vδ2 T cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells. Moreover, the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients. A new concept of cancer immunotherapy is based on the endogenous activation of γδ T cells with aminobisphosphonates plus low-dose interleukin-2.

Cells, Nov 30, 2020

Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but o... more Gamma delta (γδ) T cells are a small subset of CD3-positive T cells in the peripheral blood but occur at increased frequency in mucosal tissues. The discovery of a second T-cell receptor 35 years ago was certainly unexpected [1-4]. Looking back, however, it is obvious that the scientific interest in γδ T-cell research has been undulating since then. A breakthrough of γδ T-cell research was the discovery that the major population of human γδ T cells does not recognize peptides presented by Human Leukocyte Antigen (HLA) molecules (like the conventional CD4 + or CD8 + T cells carrying the αβ T-cell receptor) but rather recognize nonpeptidic phosphorylated molecules secreted by bacteria [5]. Such "phosphoantigens" have been discovered not only in many bacteria and some parasites but also in eukaryotic cells as intermediates of the mevalonate pathway of cholesterol synthesis [6]. Overproduction of phosphoantigens in tumor cells due to a dysregulated mevalonate pathway has been shown to activate tumor-reactive γδ T cells [7]. How such phosphoantigens are recognized by γδ T cells has been a mystery for many years. A landmark paper by Harly and colleagues identified an indispensable role of the butyrophilin family transmembrane molecules, specifically butyrophilin (BTN) 3A1 [8]. Exciting new studies have recently highlighted a similarly indispensable role of another BTN member, BTN2A1 [9,10]. Other studies have shown that BTN-like molecules are also very important for the regulation of tissue-resident human γδ T cells [11]. Taken together, there has been tremendous recent progress in the elucidation of the molecular pathways of how γδ T cells (as opposed to conventional αβ T cells) are activated and influenced by the local micromilieu. From a translational perspective, the potential advantage of γδ T cells for (cancer) immunotherapy has long been recognized. The more detailed knowledge of how γδ T cells recognize transformed cells independently of HLA restriction has certainly fueled this interest, as reflected by the increasing number of companies devoted to clinical exploration of γδ T-cell immunotherapy [12]. This Special Issue of Cells comprises 17 original papers and review articles on various aspects of γδ T cells in health and disease. In view of the recent and exciting progress in the field, I thought that this would be a wonderful time to collect contributions from leading experts to share their results and amazing new insights with the scientific community. While preparing this Special Issue, we had to mourn the sudden death of Wendy Havran, a giant in the field of γδ T-cell research and an exceptional and close friend to many of us in the γδ T-cell world. I appreciate the support of the publishers to devote this Special Issue to the memory of Professor Wendy Havran. The first paper is an appraisal of Professor Wendy Havran, written by her long-term associate Deborah Witherden. This short editorial illustrates the extraordinary personality of Wendy Havran both as a scientist and as a mentor for a large number of trainees in her lab, many of whom have moved on to take leadership positions at universities or in industry [13]. Four reviews and two original papers in this Special Issue concentrate on characteristics of γδ T cells under physiologic conditions, and how γδ T cells are activated and interact with other immune cells. Fonseca and colleagues present a thorough phenotypic analysis of γδ T cells in a population of 30 Caucasian blood donors with a mean age of 47 years. Even though this is a relatively small cohort,

International Immunology, Jan 24, 2018

It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, ... more It is widely accepted that cytotoxic T and NK cells store effector proteins including granzymes, perforin and Fas ligand (FasL) in intracellular granules, often referred to as secretory lysosomes. Upon target cell encounter, these organelles are transported to the cytotoxic immunological synapse, where they fuse with the plasma membrane to release the soluble effector molecules and to expose transmembrane proteins including FasL on the cell surface. We previously described two distinct species of secretory vesicles in T and NK cells that differ in size, morphology and protein loading, most strikingly regarding FasL and granzyme B. We now show that the signal requirements for the mobilization of one or the other granule also differ substantially. We report that prestored FasL can be mobilized independent of extracellular Ca 2+ , whereas the surface exposure of lysosome-associated membrane proteins (Lamps; CD107a and CD63) and the release of granzyme B are calcium-dependent. The use of selective inhibitors of actin dynamics unequivocally points to different transport mechanisms for individual vesicles. While inhibitors of actin polymerization/ dynamics inhibit the surface appearance of prestored FasL, they increase the activation-induced mobilization of CD107a, CD63 and granzyme B. In contrast, inhibition of the actin-based motor protein myosin 2a facilitates FasL-, but impairs CD107a-, CD63-and granzyme B mobilization. From our data, we conclude that distinct cytotoxic effector granules are differentially regulated with respect to signaling requirements and transport mechanisms. We suggest that a T cell might 'sense' which effector proteins it needs to mobilize in a given context, thereby increasing efficacy while minimizing collateral damage.

The Journal of Immunology

Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor... more Nonreceptor protein tyrosine kinases and associated substrates play a pivotal role in Ag receptor stimulation of resting cells and in the initiation of activation-induced cell death (AICD) of preactivated T cells. CD4-associated p56lck has been implicated not only in the activation of primary T cells, but also in the inhibition of T cell responses. We have previously shown that CD4+ T cell clones can be rescued from AICD when surface CD4 is engaged before the TCR stimulus. In this study, we show that prevention of AICD is associated with a CD4-dependent inhibition of TCR-triggered tyrosine phosphorylation of the Src homology 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and Vav. We provide evidence for a SLP-76 interaction with Src homology 3 domains of p56lck and identify amino acids 185–194 of SLP-76 as relevant docking site. In view of the multiple functions of p56lck and SLP-76/Vav in the initiation of TCR/CD3/CD4 signaling, we propose a model for the CD4-dependent in...

The Journal of Immunology

The gamma delta TCR is expressed on 1 to 5% of CD3+ human peripheral blood T lymphocytes. The maj... more The gamma delta TCR is expressed on 1 to 5% of CD3+ human peripheral blood T lymphocytes. The majority of peripheral blood gamma delta T cells expresses V gamma 9 paired with V delta 2; this subset strongly responds to certain microbial ligands. Other gamma delta T cell subsets with unknown Ag specificity expressing different V gamma elements are present in peripheral blood and lymphoid tissue. We describe a new anti-human V gamma mAb termed 23D12 with unusual specificity. As revealed by analysis of a large number of T cell clones and transfectants expressing molecularly well-defined gamma delta TCR, mAb 23D12 recognized several, but not all, members of the human V gamma 1 family, specifically V gamma 2, V gamma 3, and V gamma 4 but not V gamma 5 or V gamma 8. In combination with available mAb against V gamma 4, mAb 23D12 was used to identify V gamma 2- or V gamma 3-bearing cells. On average, 23D12+ cells accounted for 18% of peripheral blood gamma delta T cells and 56% of postnatal...

Journal of Leukocyte Biology

Weissmann wrote as early as 1889 that higher organisms contain within themselves the germs of dea... more Weissmann wrote as early as 1889 that higher organisms contain within themselves the germs of death [1]. However, the term, programmed cell death, or apoptosis as it is now known, was defined much later [2]. Thus, it was long recognized that damaged and old cells are eliminated within the body, but the underlying mechanisms are only now beginning to emerge. Apoptosis appears central to the process of negative selection of developing T-cells in the thymus. In regard to organ transplantation, apoptosis contributes to graft rejection and the establishment of graft tolerance. Thus, understanding the regulatory mechanisms of apoptosis may help establish a new protocol for the induction of transplantation tolerance.

Cellular & Molecular Immunology

Oncotarget, 2016

Previously, the expression of a non-secreted IL-4 variant (IL-4δ 13) has been described in associ... more Previously, the expression of a non-secreted IL-4 variant (IL-4δ 13) has been described in association with apoptosis and age-dependent Th2 T-cell polarization. Signaling pathways involved in this process have so far not been studied. Here we report the induction of IL-4δ 13 expression in human γδ T-cells upon treatment with a sublethal dose of histone deacetylase (HDACi) inhibitor valproic acid (VPA). Induction of IL-4δ 13 was associated with increased cytoplasmic IL-4Rα and decreased IL-4 expression, while mRNA for mature IL-4 was concomitantly down-regulated. Importantly, only the simultaneous combination of apoptosis and necroptosis inhibitors prevented IL-4δ 13 expression and completely abrogated VPA-induced global histone H3K9 acetylation mark. Further, our work reveals a novel involvement of transcription factor c-Jun in the signaling network of IL-4, HDAC1, caspase-3 and mixed lineage kinase domain-like protein (MLKL). This study provides novel insights into the effects of epigenetic modulator VPA on human γδ T-cell differentiation.

Cellular & molecular immunology, 2014

Cellular & molecular immunology, 2013

The elusive task of defining the character of γδ T cells has been an evolving process for immunol... more The elusive task of defining the character of γδ T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the α and β T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, γδ T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and αβ T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm γδ T cells excel thanks to their highly empathetic nature. This review gives an overview of...

The Journal of Immunology, 2006

V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the... more V(D)J rearrangements occur within loci of TCR and BCR genes, thus generating the diversity of the AgR repertoire. In addition, interlocus V(D)J rearrangements occur, giving rise to so-called “trans-rearrangements.” Such trans-rearrangements increase the diversity of the immune receptor repertoire and can be expressed as functional chimeric TCR proteins on the surface of T cells. Although chimeric receptors are not pathogenic per se, the frequency of AgR trans-rearrangements correlates with the level of genetic instability and thus could be used as a predictive biomarker for lymphoma risk.

The Journal of experimental medicine, 1991

We have previously reported that peripheral blood gamma/delta + T cells proliferate in high frequ... more We have previously reported that peripheral blood gamma/delta + T cells proliferate in high frequency (1 in 2-20) in response to heat-killed Mycobacterium tuberculosis (M.tb.). In the present study, the T cell receptor phenotype of mycobacteria-responsive human gamma/delta + T cells was analyzed in primary cultures with a set of monoclonal antibodies (mAbs) directed against V gamma 9, V delta 1, and V delta 2. When unseparated T cells were stimulated with M.tb., all proliferating gamma/delta + T cells expressed V gamma 9 (and V delta 2) after culture. Selective depletion of V gamma 9-bearing cells before culture completely abolished the proliferative response of all gamma/delta + cells (but did not inhibit reactivity of alpha/beta + T cells). In addition, when CD4- CD8- thymocytes were stimulated with M.tb., there was again selective outgrowth of V gamma 9+ cells. In this case, the starting responder population contained few (0.5-1.8%) V gamma 9+ and many (11.5-31.5%) V delta 1+ cel...

The Journal of experimental medicine, 1989

It is generally believed that CD2 (T11, sheep erythrocyte receptor) is expressed on all human T c... more It is generally believed that CD2 (T11, sheep erythrocyte receptor) is expressed on all human T cells. In the present study we have identified and characterized a minor subset of CD2- CD3/TCR alpha/beta+ T cells in the peripheral blood of healthy individuals. CD2-CD3+ T cells were enriched in PBMC depleted of plastic-adherent macrophages, E-rosetting (i.e., CD2+) T cells and surface Ig+ B cells. CD2-CD3+ T cells accounted for 0.1-0.8% of PBMC in six individuals. IL-2-dependent long-term clones of CD2-CD3+ T cells neither reacted with a panel of anti-CD2 mAbs nor expressed detectable levels of CD2 mRNA by Northern blot analysis. These clones, however, expressed a full-length TCR C beta mRNA and reacted with mAbs against TCR-alpha/beta, CD3, and CD4, and thus were mature T cells. CD2-CD3/TCR+ T cell clones could be triggered into proliferation, IL-2 production, and cytotoxic effector activity by anti-CD3 and anti-TCR mAbs. We conclude that (a) a minor subset of CD2-, CD3/TCR-alpha/bet...

International Immunology, 2009

Activation of resting T cells in vitro is triggered by combined TCR and CD28 engagement and can b... more Activation of resting T cells in vitro is triggered by combined TCR and CD28 engagement and can be modulated by simultaneous ligation of various other surface receptors. Although the Fas ligand (FasL) is best known for its capacity to initiate cell death in Fas-bearing cells, it has recently been implicated in the regulation of T cell activation. Thus, a cross-talk between the TCR and FasL is likely, but far from being biochemically elucidated. We now report that FasL engagement by immobilized but not soluble FasFc fusion protein and anti-FasL polyclonal antibody blocks the activation of human peripheral T cells even in the presence of CD28 co-stimulation. The data presented here stress the importance of the Fas/FasL system for signal initiation via the TCR-CD3 complex and provide further arguments for a retrograde signaling capacity of FasL or a crucial role of Fas as a co-stimulatory molecule.

Immunology, 1998

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown aetiology. Recently, superan... more Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown aetiology. Recently, superantigens have been implied in the pathogenesis of RA. Superantigens activate a large fraction of T cells leading to the production of cytokines and proliferation. In addition, superantigens direct cellular cytotoxicity towards major histocompatibility complex (MHC) class II‐expressing cells. There is now increasing evidence that cytotoxic T cells may be involved in the pathogenesis of RA. In the inflamed synovia class II‐positive synovial fibroblasts (SFC) are found. In the present study it was tested whether MHC class II‐positive SFC serve as target cells for superantigen‐induced cellular cytotoxicity. SFC were stimulated with interferon‐γ to express class II antigens, then they were cultivated in the presence of CD4‐positive T cells with or without staphylococcal enterotoxins (SE). Cytotoxicity of T cells was measured as release of lactate dehydrogenase from SFC. Specific cytotoxicity wa...

F1000 - Post-publication peer review of the biomedical literature, 2017

Innate T cells are a heterogeneous group of αβ and γδ T cells that respond rapidly (<2 h) upon ac... more Innate T cells are a heterogeneous group of αβ and γδ T cells that respond rapidly (<2 h) upon activation. These innate T cells also share a non MHC class I or II restriction requirement for antigen recognition. Three major populations within the innate T cell group are recognized, namely, invariant NKT cells, mucosal associated invariant T cells, and gamma delta T cells. These cells recognize foreign/self-lipid presented by non-classical MHC molecules, such as CD1d, MR1, and CD1a. They are activated during the early stages of bacterial infection and act as a bridge between the innate and adaptive immune systems. In this review, we focus on the functional properties of these three innate T cell populations and how they are purposed for antimicrobial defense. Furthermore, we address the mechanisms through which their effector functions are targeted for bacterial control and compare this in human and murine systems. Lastly, we speculate on future roles of these cell types in therapeutic settings such as vaccination.

European Journal of Immunology, 2019

F1000 - Post-publication peer review of the biomedical literature, 2017

Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing pri... more Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill-defined. We examined lysis mediated by human Vγ9Vδ2 T effectors in response to the naturally-occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cellpermeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate (POM 2-C-HMBP). CD27+/CD45RA− Th1-like effector cells killed K562 target cells though a mechanism that could be enhanced by either compound or TCR antibody and blocked by Src inhibition or BTN3A1 disruption. Pre-treatment at 4°C decreased HMBPP-induced lysis but did not reduce lysis induced by POM 2-C-HMBP. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 T effectors. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by smallmolecule induction of BTN3A1.

F1000 - Post-publication peer review of the biomedical literature, 2017

γδ T cells are one of the three immune cell types that express antigen receptors. They contribute... more γδ T cells are one of the three immune cell types that express antigen receptors. They contribute to lymphoid antitumor surveillance and bridge the gap between innate and adaptive immunity. γδ T cells have the capacity of secreting abundant cytokines and exerting potent cytotoxicity against a wide range of cancer cells. γδ T cells exhibit important roles in immune-surveillance and immune defense against tumors and have become attractive effector cells for cancer immunotherapy. γδ T cells mediate anti-tumor therapy mainly by secreting pro-apoptotic molecules and inflammatory cytokines, or through a TCR-dependent pathway. Recently, γδ T cells are making their way into clinical trials. Some clinical trials demonstrated that γδ T cell-based immunotherapy is well tolerated and efficient. Despite the advantages that could be exploited, there are obstacles have to be addressed for the development of γδ T cell immunotherapies. Future direction for immunotherapy using γδ T cells should focus on overcoming the side effects of γδ T cells and exploring better antigens that help stimulating γδ T cell expansion in vitro.

Frontiers in Immunology, 2015

F1000 medicine reports, 2010

γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against... more γδ T lymphocytes are a numerically small subset of T cells with potent cytotoxic activity against a variety of tumor cells. Human γδ T cells expressing the Vγ9Vδ2 T cell antigen receptor recognize endogenous pyrophosphate molecules that are overproduced in transformed cells. Moreover, the intracellular accumulation of such pyrophosphates is strongly enhanced by aminobisphosphonates used in the treatment of osteoporosis and bone metastasis in certain cancer patients. A new concept of cancer immunotherapy is based on the endogenous activation of γδ T cells with aminobisphosphonates plus low-dose interleukin-2.