Thymosin 1: An Endogenous Regulator of Inflammation, Immunity, and Tolerance (original) (raw)
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Thymosin α 1 An endogenous regulator of inflammation, immunity, and tolerance
Annals of the New York Academy of Sciences, 2007
Thymosin ␣1 (T␣1), first described and characterized by Allan Goldstein in 1972, is used worldwide for the treatment of some immunodeficiencies, malignancies, and infections. Although T␣1 has shown a variety of effects on cells and pathways of the immune system, its central role in modulating dendritic cell (DC) function has only recently been appreciated. As DCs have the ability to sense infection and tissue stress and to translate collectively this information into an appropriate immune response, an action on DCs would predict a central role for T␣1 in inducing different forms of immunity and tolerance. Recent results have shown that T␣1: (a) primed DCs for antifungal Th1 resistance through Toll-like receptor (TLR)/MyD88-dependent signaling and this translated in vivo in protection against aspergillosis; (b) activated plasmacytoid DCs (pDC) via the TLR9/MyD88-dependent viral recognition, thus leading to the activation of interferon regulatory factor 7 and the promotion of the IFN-␣/IFN-␥−dependent effector pathway, which resulted in vivo in protection against primary murine cytomegalovirus infection; (c) induced indoleamine 2,3-dioxygenase activity in DCs, thus affecting tolerization toward self as well as microbial non-self-antigens, and this resulted in vivo in transplantation tolerance and protection from inflammatory allergy. T␣1 is produced in vivo by cleavage of prothymosin ␣ in diverse mammalian tissues. Our data qualify T␣1 as an endogenous regulator of immune homeostasis and suggest that instructive immunotherapy with T␣1, via DCs and tryptophan catabolism, could
Blood, 2006
Thymosin ␣1 (T␣1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immunosuppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined T␣1 for possible induction of DC-dependent regulatory effects. T␣1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by T␣1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, T␣1-primed DCs fulfilled multiple requirements, in-cluding the induction of T-helper type 1 immunity within a regulatory environment. Thus, instructive immunotherapy with T␣1 targeting IDO-competent DCs could allow for a balanced control of inflammation and tolerance. (Blood. 2006;108:2265-2274)
Blood, 2006
Thymosin α1 (Tα1), a naturally occurring thymic peptide, primes dendritic cells (DCs) for antifungal T-helper type 1 resistance through Toll-like receptor 9 (TLR9) signaling. As TLR9 signaling also activates the immuno-suppressive pathway of tryptophan catabolism via indoleamine 2,3-dioxygenase (IDO), we examined Tα1 for possible induction of DC-dependent regulatory effects. Tα1 affected T-helper cell priming and tolerance induction by human and murine DCs and induced IDO expression and function in the latter cells. IDO activation by Tα1 required TLR9 and type I interferon receptor signaling and resulted in interleukin-10 production and generation of regulatory T cells. In transfer experiments, functionally distinct subsets of differentiated DCs were required for priming and tolerance to a fungal pathogen or alloantigens. In contrast, Tα1-primed DCs fulfilled multiple requirements, including the induction of T-helper type 1 immunity within a regulatory environment. Thus, instructive...
IFN- -rich environment programs dendritic cells toward silencing of cytotoxic immune responses
Journal of Leukocyte Biology, 2014
Lately, there is increasing evidence that emphasizes the regulatory functions of IFN-␥, which serve as negative-feedback mechanisms after, e.g., pathogen clearance, to prevent unnecessary tissue destruction. Inflammatory processes involving Th1 and cytotoxic responses are characterized by high, local IFN-␥ concentrations, followed by resolution and immune silencing. Although this is a well-known course of events, extensive attempts to address potential differential effects of IFN-␥ in the manner of its availability (quantitatively) in the environment do not exist. We demonstrate that high doses of IFN-␥ do not induce DC maturation and activation but instead, induce specific regulatory characteristics in DCs. Considering their phenotype, high doses of IFN-␥ extensively induce the expression of ILT-4 and HLA-G inhibitory molecules. Interestingly, the well-known priming effect of IFN-␥ for IL-12p70 production is lost at these conditions, and the DC cytokine profile is switched toward an increased IL-10/IL-12p70 ratio upon subsequent stimulation with CD40L. Furthermore, such DCs are capable of silencing cellular immune responses and activation of cytotoxic CD8 ϩ T lymphocytes, resulting in reduced cell proliferation and down-regulation of granzyme B expression. Additionally, we find that in this manner, immune regulation mediated by IFN-␥ is not mainly a result of increased enzymatic activity of IDO in DCs but rather, a result of HLA-G signaling, which can be reversed by blocking mAb. Altogether, our results identify a novel mechanism by which a Th1-like environment programs the functional status of DCs to silence ongoing cytotoxic responses to prevent unwanted tissue destruction and inflammation. J. Leukoc. Biol. 95: 000 -000; 2014.
Dendritic Cells are Both Targets and Initiators of Peripheral Immune Tolerance to Self
2013
Mucin 1 (MUC1) is a highly glycosylated membrane-bound protein normally expressed on the apical surface of ductal epithelial cells. During malignant transformation MUC1 acts as a Tumor-Associated Antigen (TAA) by virtue of its overexpression, loss of polarity, and hypoglycosylation, allowing for T cell and antibody recognition of cryptic peptide epitopes derived from its extracellular domain. Almost all adenocarcinomas express abnormal MUC1 making it an attractive target for cancer vaccines. However, vaccination of MUC1.Tg mice with a synthetic, unglycosylated MUC1 peptide (MUC1p) that mimics one tumor form of the molecule results in a weak anti-MUC1p immune response. WT mice receiving the same vaccine generate robust immunity to MUC1p, suggesting that it is viewed as a "self" antigen in MUC1.Tg mice, and apparently subject to peripheral tolerance. To globally query these distinct programs of immunity and tolerance induced by MUC1p in WT and MUC1.Tg mice respectively, we conducted whole transcriptome analysis of splenic RNA 24h and 72h after i.v. immunization of both mouse strains with MUC1p. We found that a new cohort of "pancreatic" enzymes (e.g. trypsin and CPB1) were expressed by splenic dendritic cells (DC) and regulated such that immunization with self-antigen suppressed their expression while foreign-antigens induced it within 24h post-vaccination. The relative expression of trypsin and CPB1 was highly correlated with the immunogenicity of the DC. Suppressed expression marked DC that were highly tolerized as demonstrated by low costimulatory molecule expression, limited motility, production of Aldh1/2, and preferential priming of naïve CD4 + T cells into Foxp3 + Treg versus IFNγ + cells, while enhanced expression identified immunogenic DC. Deficient NFκβ pathway activation and enhanced STAT3 phosphorylation transcriptionally underlie tolerized DC along v with sustained expression of zDC. Trypsin was required for efficient degradation of the extracellular matrix, while CPB1 was required by DC to induce optimal, antigen-specific proliferation of CD4 + T cells. Importantly, these vaccine-induced changes in DC phenotype affected the entire splenic DC compartment, revealing an underappreciated role for endogenous DC in the transmission and amplification of vaccine-induced immunity or tolerance. These results underscore the importance of vaccine antigen choice and will contribute to rational vaccine design. vi TABLE OF CONTENTS
Immunology Letters, 2007
Although thymosins have been demonstrated to have immunomodulatory effects, it is still not clear whether they could affect dendritic cells (DCs), the most professional antigen-presenting cells. The objective of this study was to determine the effect and potential mechanisms of thymosin-α1 (Tα1) on DC differentiation and functional maturation. Human peripheral blood CD14 + monocytes were purified by using a magnetic separation column and cultured with GM-CSF and IL-4 to differentiate into immature DCs (iDCs). In the presence of Tα1, iDC surface markers CD40, CD80, MHC class I and class II molecules were significantly upregulated as measured by flow cytemotry analysis. However, Tβ4 or Tβ10 did not show these effects on iDCs. There was approximately a 30% reduction in antigen (FITC-conjugated dextran)-uptake by Tα1-treated iDCs as compared with non-Tα1-treated iDCs. In addition, Tα1-treated matured DCs (mDCs) showed an increased stimulation of allogeneic CD3 + T-cell proliferation as measured by a mixed-lymphocyte reaction assay. Tα1-treated mDCs also increased the production of several Th1-and Th2-type cytokines as measured by a Bio-Plex cytokine assay. Furthermore, rapid activation of p38 MAPK and NFκB was seen in Tα1-treated iDCs as measured by a Bio-Plex phosphoprotein assay. Tα1 significantly enhances on DC differentiation, activation and functions from human peripheral blood CD14 + monocytes possiblly through a mechanism of the activation of p38 MAPK and NFκB pathways. This study provides a basis to further evaluate Tα1 as a possible adjuvant for a DC-directed vaccine or therapy.
Natural adjuvants: Endogenous activators of dendritic cells
Nature Medicine, 1999
The stimuli that activate dendritic cells 1-4 (DCs), and thereby initiate immune responses, are the subjects of intense study, not only because they are crucial for the production of more effective adjuvants for use in vaccines, but also because they are essential to the initiation of transplant rejection, tumor immunity, autoimmunity and the immunobiology of the maternal-fetal interface.
Taking dendritic cells into medicine
Nature, 2007
Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumors can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but again DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy. Immunology is a major force in medicine. It is needed to understand how prevalent diseases (Fig. 1) come about and how to develop preventions and treatments. This broad reach of the immune system reflects its two functions: to recognize diverse substances termed antigens, and to generate many qualitatively distinct responses. Dendritic cells (DCs), named for their probing, tree-like or dendritic shapes (Gr. dendron, tree) 1,2 (Fig. 1), are pivotal for both: recognition of a universe of antigens and control of an array of responses. Previously, we reviewed some biological features of DCs 3,4. Here we illustrate medical implications of DCs, which control a spectrum of innate and adaptive responses. Innate immunity encompasses many rapid reactions to infection and other challenges 5-9. Adaptive immunity, in contrast, is learned or acquired more slowly, in days to weeks; it has two hallmarks: exquisite specificity for antigens, and a durable memory to develop improved function upon reexposure to antigen. Adaptive responses are either immunogenic, providing resistance in infection and cancer, or tolerogenic, leading to silencing as is desirable in transplantation, autoimmunity and allergy. To date, the successes of immunology in the clinic have largely been based on antibodies made by B cells, but T cell-mediated immunity, which has enormous yet untapped therapeutic potential will be stressed here. DCs are specialized to capture and process antigens in vivo 10-14 , converting proteins to peptides that are presented on MHC molecules and recognized by T cells. DCs also migrate to T cell areas of lymphoid organs where the two cell types interact to bring about clonal selection 15-17. The DC system is thus designed to harness the recognition repertoire of T cells, consisting of billions of different lymphocytes, each with a distinct but randomly arranged antigen receptor 18. This repertoire in turn represents a virtually infinite "drug library" for specific therapies that increase or decrease T cell function. Following clonal selection, DCs control many T cell responses. Antigen-selected T cells undergo extensive expansion, a thousand fold or more as a result of division at a rate as high as 2-3 cell cycles a day 19,20. Clones of lymphocytes are also subject to silencing or tolerance by socalled "tolerogenic DCs" 21-23 , which either eliminate (delete) 19,20,23-26 or block (suppress) T cells 27-39. If deletion is avoided, the clone undergoes differentiation to bring about an array of potential helper, killer, and suppressive activities. For example, under the control of DCs, helper T cells acquire the capacity to produce powerful cytokines like interferon-γ to activate macrophages to resist infection with facultative and obligate intracellular microbes (Th1 cells) 40-44 , or IL-4, 5 and 13 to mobilize white cells that resist helminths (Th2 cells) 45,46 , or IL-17 to mobilize phagocytes at body surfaces to resist extracellular bacilli (Th17 cells) 47-51. Alternatively, DCs can guide T cells to become suppressive by making IL-10 (Tr1 cells) 28,30,52,53 or by differentiating into foxp3 + cells 36,37,39. Finally, DCs induce the T cell clone to acquire memory, allowing it to persist for prolonged periods and to respond rapidly to a repeated exposure to antigen 54-58. Box 1, Location of DCs. DCs are a uniquely positioned, prime target for disease relevant stimuli. DCs are abundant at body surfaces like skin, pharynx, upper esophagus, vagina, ectocervix, and anus 419 , and at so called internal or mucosal surfaces, such as the respiratory and gastro-intestinal systems 61,62,364,420-423. DCs actually extend their processes through the tight junctions of epithelia, which likely involves DC expression of the tight junction proteins claudens and occludens, without altering epithelial barrier function 424. This increases DC capture of antigens from the environment 61,163 even when there is no overt infection or inflammation, probably allowing for the silencing of the immune system to harmless environmental antigens 26,363. DCs at body surfaces can function locally, e.g., to convert vitamins A and D to active retinoic acid and 1,25(OH) 2 D 3. One consequence of the overlooked metabolic capacities of DCs is to increase the homing of immune cells to that mucosal surface 425-427 and, in the case of retinoic acid, to help DCs differentiate suppressor T cells that block autoimmune and inflammatory conditions 428-431. After leaving peripheral tissues, DCs migrate with environmental, self, and microbial antigens to lymphoid organs, a process that is guided by chemokines 15,17 and can be enhanced by vaccination 432,433. DCs have now been studied in intact lymphoid tissues without the need for cell isolation. These are the sites where immune resistance and tolerance are initiated. The DCs create a labyrinthine system within T cell areas, while probing the environment through the continuous formation and retraction of processes 63 and displaying antigens and other stimuli needed to initiate responses by appropriate clones of specific T cells 434-438. New research reveals interactions of DCs in lymphoid tissues with other major classes of lymphocytes, B cells 423,439-448 and NK cells 257,260,261,449. Microbes also can alter the function of DCs so that they switch T cell responses from protective Th1 to nonprotective Th2, as in infections with Aspergillus fumigatus 140,141 malaria 142 , and hepatitis C 143 , or to IL-10 production in the case of Bordetella pertussis 144. At this time, there are no therapies that try to interrupt the microbial immune evasion pathways that are summarized above. Several microbes additionally can exploit DCs for purposes of replication and spread in the infected host. The lectin DC-SIGN/CD209 is used by dengue virus 145,146 and Ebola virus 147 to infect DCs. In the case of HIV-1, CMV, and Ebola virus, the lectin additionally sequesters virus within DCs, which later transmit infectious virus to other targets like T cells 147-153. DCs are
Novel molecular mechanisms of dendritic cell-induced T cell activation
International Immunology, 2000
Human peripheral blood DC (PBDC) were derived by 2 h adhesion followed by 7 day culture in a combination of granulocyte macrophage colony stimulating factor and IL-4, and depletion of residual T and B cells. These PBDC were used to induce autologous T cell proliferation in a CD3-dependent response, and antibodies against CD11a/18 and CD86 were used as control inhibitors of accessory function. Antibodies against five of the cell surface molecules that we have recently identified on the surface of DC, CD13, CD87, CD98, CD147 and CD148, and an antibody which recognizes a molecule that has not as yet been identified, all inhibited the CD3-induced T cell proliferation. These findings were observed not only when antibodies were present throughout the culture, but also when they were prepulsed on to the surface of the DC, suggesting the inhibition was mediated via the antigenpresenting cells rather than the T cell. The same set of antibodies also inhibited an allospecific mixed lymphocyte reaction, confirming that the inhibitory effect was not dependent on the use of a CD3 antibody as the stimulating agent. All the antibodies of known specificity inhibited both CD4 and CD8 T cells equally. Unlike CD87, CD98 and CD147 antibodies, which inhibited activation of both CD45RA (naive) T cells and CD45RO (memory) T cells, CD13 and CD148 appeared to be involved in activation of naive cells only. The molecules identified in this study have not previously been demonstrated to play a role as accessory molecules on DC, the cells that are pivotal for immune induction. Therefore they may provide new potential targets for modulation of the immune response at the APC level.
International Immunology, 2005
Murine plasmacytoid dendritic cells (pDCs) have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) function and mediate immunosuppression in specific settings; yet, the conditions of spontaneous versus induced activity have remained unclear. We have used maneuvers known to up-regulate IDO in different cell types and have examined the relative efficacy and mechanisms of the induced activity in splenic pDCs, namely, after specific receptor engagement by CTLA-4-Ig, CD200-Ig or CD28-Ig, the latter in combination with silenced expression of the suppressor of cytokine signaling 3 (SOCS3) gene. We found that pDCs (CD11c 1 mPDCA-1 1 120G8 1 ) do not express IDO and are not tolerogenic under basal conditions. B7-1 engagement by CTLA-4-Ig, CD200R1 engagement by CD200-Ig and B7-1/B7-2 engagement by CD28-Ig in SOCS3-deficient pDCs were each capable of initiating IDO-dependent tolerance via different mechanisms. IFN-c was the major cytokine responsible for CTLA-4-Ig effects, and type I IFNs for those of CD200-Ig. Immunosuppression by CD28-Ig in the absence of SOCS3 required IFN-c induction and IFN-like actions of IL-6. Therefore, although pDCs do not mediate IDO-dependent tolerance constitutively, multiple ligands and cytokines will contribute to the expression of a tolerogenic phenotype by pDCs in the mouse.