David Kugler | Benaroya Research Institute (original) (raw)
Papers by David Kugler
The Journal of Immunology
Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been... more Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been implicated in transducing signals mediated by IL-12, IL-23 and IFNα. A strain of mice (B10.Q/J) bears a missense mutation in the pseudokinase domain of Tyk2 which renders the kinase nonfunctional. These mice were initially identified by their heightened resistance to collagen-induced arthritis (CIA) and impaired response to IL-12 and type I IFNs. Following in-house confirmation of disease resistance to CIA, B10.Q/J and wild-type (WT) mice were injected with PBS, IL-12, IL-18, or IL-12+IL-18. Sera were collected at 2 and 24 hours post-injection, and levels of various polypeptide mediators were determined by multi-analyte profiling and ELISA. Compared to WT mice, the absence of functional Tyk2 in the B10.Q/J mice lead to a decrease in circulating IFNγ following IL-12+IL-18 administration. Confirmation that IFNγ output was dependent on Jak involvement was established using the Jak antagoni...
Cell Reports, 2016
Inerleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune ... more Inerleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin β 3 that is IL-23 dependent. Integrin β 3 was not upregulated on all activated T cells; rather, integrin β 3 was upregulated along with its functional partner integrin αv on effector Th17 cells and "ex-Th17" cells, and αvβ 3 hi RORγt + cells expanded during EAE. Integrin αvβ 3 inhibitors ameliorated clinical signs of EAE, and integrin β 3 deficiency on CD4 + T cells alone was sufficient to block EAE induction. Furthermore, integrin-β 3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin β 3 −/− T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin β 3 is required for Th17 cell-mediated autoimmune CNS inflammation.
The Journal of Immunology, 2008
Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation
Blood, 2017
The development of chimeric antigen receptor (CAR) T cells that target antigens expressed on the ... more The development of chimeric antigen receptor (CAR) T cells that target antigens expressed on the surface of malignant plasma cells is a promising new treatment approach for relapsed refractory multiple myeloma patients. Although early clinical trials investigating single agent anti-B cell maturation antigen (BCMA) CAR-T cells achieved clinical responses in myeloma, additional combinatorial therapies may increase the effectiveness of this treatment. Lenalidomide, a small molecule immunomodulatory agent approved for use in multiple myeloma, can have both direct tumoricidal and T cell modulatory effects. Recent publications have highlighted the ability of lenalidomide to enhance T cell and CAR-T function in preclinical models. The immunomodulatory effects of lenalidomide were investigated in combination with an autologous cellular drug product transduced to express a BCMA-specific CAR with 4-1BB costimulatory and CD3 zeta endodomains. The intrinsic effects mediated by lenalidomide on C...
IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that play... more IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.
The Journal of Immunology, 2016
Activation of TGF-b by dendritic cells (DCs) expressing avb8 integrin is essential for the genera... more Activation of TGF-b by dendritic cells (DCs) expressing avb8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that avb8 integrin is preferentially expressed by CD103 + DCs and confers their ability to activate TGF-b and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that b8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-b itself, along with retinoic acid and TLR signaling, drives expression of avb8 in DCs. However, these signals only result in high levels of b8 expression in cells of the cDC1 lineage, CD8a + , or CD103 + CD11b 2 DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory avb8-expressing DCs specialized for activation of TGF-b to facilitate Treg generation.
Scientific Reports
T cell activation is a cornerstone in manufacturing of T cell-based therapies, and precise contro... more T cell activation is a cornerstone in manufacturing of T cell-based therapies, and precise control over T cell activation is important in the development of the next generation T-cell based therapeutics. This need cannot be fulfilled by currently available methods for T cell stimulation, in particular not in a time dependent manner. Here, we describe a modular activation reagent called Expamers, which addresses these limitations. Expamers are versatile stimuli that are intended for research and clinical use. They are readily soluble and can be rapidly bound and removed from the cell surface, allowing nearly instantaneous initiation and termination of activation signal, respectively. Hence, Expamers enable precise regulation of T cell stimulation duration and provide promise of control over T cell profiles in future products. Expamers can be easily adopted to different T cell production formats and have the potential to increase efficacy of T cell immunotherapeutics.
Molecular Cancer Therapeutics
The Journal of experimental medicine, Dec 12, 2016
Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory po... more Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4(+) Th1 cells but also a persistent decrease in the size of the naive CD4(+) T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ. Importantly, the resulting quantitative and qualitative deficiency in naive CD4(+) T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. These findings reveal that systemic infectious agents, such as T. gondii, can induce long-term...
The Journal of Immunology, Apr 1, 2009
Journal of immunology (Baltimore, Md. : 1950), 2006
IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that play... more IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.
Immunity, 2014
Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription... more Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription factors, but how these integrate with posttranscriptional and epigenetic programs to regulate gene expression is poorly understood. Here we found defective Th17 cell cytokine expression in miR-155-deficient CD4+ T cells in vitro and in vivo. Mir155 was bound by Th17 cell transcription factors and was highly expressed during Th17 cell differentiation. miR-155-deficient Th17 and T regulatory (Treg) cells expressed increased amounts of Jarid2, a DNA-binding protein that recruits the Polycomb Repressive Complex 2 (PRC2) to chromatin. PRC2 binding to chromatin and H3K27 histone methylation was increased in miR-155-deficient cells, coinciding with failure to express Il22, Il10, Il9, and Atf3. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2.
The Journal of Immunology
Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been... more Tyrosine kinase 2 (Tyk2), a member of the Jak family of non-receptor associated kinases, has been implicated in transducing signals mediated by IL-12, IL-23 and IFNα. A strain of mice (B10.Q/J) bears a missense mutation in the pseudokinase domain of Tyk2 which renders the kinase nonfunctional. These mice were initially identified by their heightened resistance to collagen-induced arthritis (CIA) and impaired response to IL-12 and type I IFNs. Following in-house confirmation of disease resistance to CIA, B10.Q/J and wild-type (WT) mice were injected with PBS, IL-12, IL-18, or IL-12+IL-18. Sera were collected at 2 and 24 hours post-injection, and levels of various polypeptide mediators were determined by multi-analyte profiling and ELISA. Compared to WT mice, the absence of functional Tyk2 in the B10.Q/J mice lead to a decrease in circulating IFNγ following IL-12+IL-18 administration. Confirmation that IFNγ output was dependent on Jak involvement was established using the Jak antagoni...
Cell Reports, 2016
Inerleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune ... more Inerleukin-23 (IL-23) is required for inflammatory Th17 cell function in experimental autoimmune encephalomyelitis (EAE), and IL-23 blockade reduces the number of effector Th17 cells in the CNS. We report that pro-inflammatory Th17 cells express high integrin β 3 that is IL-23 dependent. Integrin β 3 was not upregulated on all activated T cells; rather, integrin β 3 was upregulated along with its functional partner integrin αv on effector Th17 cells and "ex-Th17" cells, and αvβ 3 hi RORγt + cells expanded during EAE. Integrin αvβ 3 inhibitors ameliorated clinical signs of EAE, and integrin β 3 deficiency on CD4 + T cells alone was sufficient to block EAE induction. Furthermore, integrin-β 3-deficient Th17 cells, but not Th1 cells, were impaired in their ability to induce EAE. Integrin β 3 −/− T cells induced smaller demyelinated lesions and showed reduced spread and accumulation within the CNS, corresponding with impaired extracellular-matrix-mediated migration. Hence, integrin β 3 is required for Th17 cell-mediated autoimmune CNS inflammation.
The Journal of Immunology, 2008
Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation
Blood, 2017
The development of chimeric antigen receptor (CAR) T cells that target antigens expressed on the ... more The development of chimeric antigen receptor (CAR) T cells that target antigens expressed on the surface of malignant plasma cells is a promising new treatment approach for relapsed refractory multiple myeloma patients. Although early clinical trials investigating single agent anti-B cell maturation antigen (BCMA) CAR-T cells achieved clinical responses in myeloma, additional combinatorial therapies may increase the effectiveness of this treatment. Lenalidomide, a small molecule immunomodulatory agent approved for use in multiple myeloma, can have both direct tumoricidal and T cell modulatory effects. Recent publications have highlighted the ability of lenalidomide to enhance T cell and CAR-T function in preclinical models. The immunomodulatory effects of lenalidomide were investigated in combination with an autologous cellular drug product transduced to express a BCMA-specific CAR with 4-1BB costimulatory and CD3 zeta endodomains. The intrinsic effects mediated by lenalidomide on C...
IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that play... more IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.
The Journal of Immunology, 2016
Activation of TGF-b by dendritic cells (DCs) expressing avb8 integrin is essential for the genera... more Activation of TGF-b by dendritic cells (DCs) expressing avb8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that avb8 integrin is preferentially expressed by CD103 + DCs and confers their ability to activate TGF-b and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that b8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-b itself, along with retinoic acid and TLR signaling, drives expression of avb8 in DCs. However, these signals only result in high levels of b8 expression in cells of the cDC1 lineage, CD8a + , or CD103 + CD11b 2 DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory avb8-expressing DCs specialized for activation of TGF-b to facilitate Treg generation.
Scientific Reports
T cell activation is a cornerstone in manufacturing of T cell-based therapies, and precise contro... more T cell activation is a cornerstone in manufacturing of T cell-based therapies, and precise control over T cell activation is important in the development of the next generation T-cell based therapeutics. This need cannot be fulfilled by currently available methods for T cell stimulation, in particular not in a time dependent manner. Here, we describe a modular activation reagent called Expamers, which addresses these limitations. Expamers are versatile stimuli that are intended for research and clinical use. They are readily soluble and can be rapidly bound and removed from the cell surface, allowing nearly instantaneous initiation and termination of activation signal, respectively. Hence, Expamers enable precise regulation of T cell stimulation duration and provide promise of control over T cell profiles in future products. Expamers can be easily adopted to different T cell production formats and have the potential to increase efficacy of T cell immunotherapeutics.
Molecular Cancer Therapeutics
The Journal of experimental medicine, Dec 12, 2016
Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory po... more Because antigen-stimulated naive T cells either die as effectors or enter the activated/memory pool, continuous egress of new T lymphocytes from thymus is essential for maintenance of peripheral immune homeostasis. Unexpectedly, we found that systemic infection with the protozoan Toxoplasma gondii triggers not only a transient increase in activated CD4(+) Th1 cells but also a persistent decrease in the size of the naive CD4(+) T lymphocyte pool. This immune defect is associated with decreased thymic output and parasite-induced destruction of the thymic epithelium, as well as disruption of the overall architecture of that primary lymphoid organ. Importantly, the resulting quantitative and qualitative deficiency in naive CD4(+) T cells leads to an immunocompromised state that both promotes chronic toxoplasma infection and leads to decreased resistance to challenge with an unrelated pathogen. These findings reveal that systemic infectious agents, such as T. gondii, can induce long-term...
The Journal of Immunology, Apr 1, 2009
Journal of immunology (Baltimore, Md. : 1950), 2006
IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that play... more IL-17 is an inflammatory cytokine produced primarily by a unique lineage of CD4 T cells that plays critical roles in the pathogenesis of multiple autoimmune diseases. IL-17RA is a ubiquitously expressed receptor that is essential for IL-17 biologic activity. Despite widespread receptor expression, the activity of IL-17 is most classically defined by its ability to induce the expression of inflammatory cytokines, chemokines, and other mediators by stromal cells. The lack of IL-17 responsiveness in mouse stromal cells genetically deficient in IL-17RA is poorly complemented by human IL-17RA, suggesting the presence of an obligate ancillary component whose activity is species specific. This component is IL-17RC, a distinct member of the IL-17R family. Thus, the biologic activity of IL-17 is dependent on a complex composed of IL-17RA and IL-17RC, suggesting a new paradigm for understanding the interactions between the expanded family of IL-17 ligands and their receptors.
Immunity, 2014
Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription... more Specification of the T helper 17 (Th17) cell lineage requires a well-defined set of transcription factors, but how these integrate with posttranscriptional and epigenetic programs to regulate gene expression is poorly understood. Here we found defective Th17 cell cytokine expression in miR-155-deficient CD4+ T cells in vitro and in vivo. Mir155 was bound by Th17 cell transcription factors and was highly expressed during Th17 cell differentiation. miR-155-deficient Th17 and T regulatory (Treg) cells expressed increased amounts of Jarid2, a DNA-binding protein that recruits the Polycomb Repressive Complex 2 (PRC2) to chromatin. PRC2 binding to chromatin and H3K27 histone methylation was increased in miR-155-deficient cells, coinciding with failure to express Il22, Il10, Il9, and Atf3. Defects in Th17 cell cytokine expression and Treg cell homeostasis in the absence of Mir155 could be partially suppressed by Jarid2 deletion. Thus, miR-155 contributes to Th17 cell function by suppressing the inhibitory effects of Jarid2.