T cells and the Immune Response

 

CSIR-UGC-NET or DBT-JRF qualified candidates are welcome to apply directly to me for a PhD position. Preference will be given to candidates with an Immunology background. For other openings please refer to http://ils.res.in/devadas_group.htm T helper cell AICD modulates the Immune response The immune system organizes defence against pathogens through finely tuned innate and adaptive arms that have intricate and regimented positive and negative feedback loops. T cells come under the adaptive immune response arm and antigen presentation to these cells causes them to proliferate, produce cytokines and counter pathogen(s). Multiple factors including the presence of pathogen associated products, cytokine combinations and or their altered levels influence preferential development of antigen specific cytotoxic or helper T cells but the exact mechanisms are still being studied. It is of significance that biased T cell activation is crucial in countering infectious agents, both intra and extra cellular, that is encountered during a life time. Interestingly differentially activated T cell subsets have completely contrasting effects on the immune system and are mutually counterproductive in disease conditions when the opposite subset is required. The presence of unwanted T cell subsets have been noted in chronic diseases such as Arthritis, Asthma, AIDS, Tuberculosis and helminth infections and their persistence have been hallmarks of poor prognosis. Recent studies have shown that pathogen associated products and or loss in immune regulation seem to drive the unwanted T cell subset. Subsequently for therapeutic interventions it is critically important to remove the unwanted T cell subset and re establish the preferred T cell. To that end we will use the balance of pro and anti apoptotic proteins that are differentially regulated by cytokines and target them to attempt manipulation of the immune responses. Novel T Helper subset promotes Immune Responses through GM-CSF T helper cells are critical in maintaining immune responses but have an undefined relationship with GM-CSF, one of the most potent immune stimulatory cytokines. By depleting major cytokines during CD4+ T cells differentiation in vitro, we obtained a novel subset of T helper cells (ThGM), that produced significantly higher amounts of GM-CSF than other T helper subsets. Interestingly, ThGM cells through GM-CSF, helped cytokine production by Th1, Th2, Tc1, Tc2 and naïve T cells. DC differentiation with GM-CSF alone up regulated DC-SIGN significantly while anti-GM-CSF antibody supplementation abolished the cytokine augmentation properties of ThGM cells. Furthermore, ThGM cells are prone to AICD and express elevated levels of pro-apoptotic proteins, such Bid and Bim. Inhibitors of FasL, TRAIL, caspase 8 or granzymes could not inhibit AICD in ThGM cells. Thus, ThGM cells are a novel T helper population that produces GM-CSF, exhibits high susceptibility to apoptosis, and could play an important role in regulating immune responses. Cytotoxic T cell AICD could bias Immune Response through IL-10 Cytotoxic T cells can be differentiated into type 1 (Tc1) and type 2 (Tc2) as their T helper counterparts. Interestingly, TCR-ICD mechanisms reveal that CD95L mediates cell death in Tc1 cells while Tc2 cells require TRAIL, Bim and caspases’. Inhibiting TRAIL binding in wild type mice and Tc2 cells from TRAIL KO mice displayed altered Tc2 death while pan caspase inhibitors blocked AICD in both Tc1 and Tc2 subsets. Rescued Tc2 cells from Wild type or Tc2 TRAIL KO mice secreted significantly higher amounts of IL-10 along with IL-4 and IL-5 while Tc1 cells produced IFN- and TNF-. Interestingly chronic activation of T cells resulted in IL-10 secreting CD8 cells that dominate through FasL mediated killing of CD4 cells while CD8 T cell differentiated in the presence of IL-10 upregulated Serine Protease Inhibitors- 6 and 2A. We conclude that pathogens could alter the immune response by affecting TCR-ICD of cytotoxic T cells through IL-10 and by affecting TCR-ICD. Selected Publications Peer reviewed articles Devadas S, Das J, Liu C, Zhang L, Roberts A, Pan Z, Moore P, Das G, Shi Y. Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity. 2006 Aug; 25(2):237-47. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HS, Das G, Devadas S. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res. 2006 Feb; (2):126-33. Devadas S, Jackson SH, Jaeyul Kwon, Ligia Pinto and Mark S. Williams. T cells express an NAD(P)H oxidase that contributes to TcR stimulated generation of reactive oxygen species. Nature Immunology Aug 2004 5(8):818-27. Devadas S, Hinshaw JA, Zaritskaya L, Williams MS. Fas-stimulated generation of reactive oxygen species or exogenous oxidative stress sensitize cells to Fas-mediated apoptosis. Free Radic Biol Med. 2003 Sep 15; 35(6):648-61. Kwon J, Devadas S, Williams MS. T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med. 2003 Aug 15; 35(4): 406-17. Zhang XR, Zhang LY, Devadas S, Li L, Keegan AD, Shi YF. Reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells: role of apoptosis in T helper subset differentiation. Cell Death Differ. 2003 Feb; 10(2):203-10. Devadas S, Greeneltch KM, Yin D, Allan Mufson R, Zhou JN. Stressed to death: implication of lymphocyte apoptosis for Psychoneuroimmunology. Shi Y. Brain Behav Immun. 2003 Feb;17 Suppl 1:S18-26. Roberts AI, Devadas S, Zhang X, Zhang L, Keegan A, Greeneltch K, Solomon J, Wei L, Das J, Sun E, Liu C, Yuan Z, Zhou JN, Shi Y. The role of activation-induced cell death in the differentiation of T-helper-cell subsets. Immunol Res. 2003; 28:285-93. Devadas S, Luba Zaritskaya, Sue Goo Rhee, Larry Oberley and Mark S. Williams. Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation Selective Regulation of Mitogen-Activated Protein Kinase Activation and Fas Ligand Expression. J Exp Med 2002 Jan 7; 195 (1):59-70. Devadas S, CV Ramesh and Puvanakrishnan R. “In vitro effects of a novel tetrapeptide in human neutrophils and in a rat model of Osteoarthritis” Protein and Peptide Letters Vol 5, no5, 287-294, 1998. Poornapriya T, Meera R, Devadas S and Puvanakrishnan R. Preliminary studies on the effect of electromagnetic field in adjuvant induced arthritis in rats. Medical Science Research 26: 467-469, 1998.Devadas S, Das J, Liu C, Zhang L, Roberts A, Pan Z, Moore P, Das G, Shi Y. Granzyme B is critical for T cell receptor-induced cell death of type 2 helper T cells. Immunity. 2006 Aug; 25(2):237-47. Book Publication Shi, YF, Devadas, S, Zhang, XR, Zhang, LY, Keegan, A, Greeneltch, K, Solomon, JC, Yuan, ZR, Sun, EW, Liu, C, Das, J, Thayyil-Satish, M, Wei, LX, Zhou, JN and Roberts, A, Activation-Induced Cell Death and T Helper Subset Differentiation. In Shi, Y. F., Cidlowski, J., Scott, D. W. and Shi, Y. B. (Eds.) Molecular Mechanisms of Programmed Cell Death. Kluwer Academic/Plenum Publishers, New York 2003. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR, Tan HS, Das G, Devadas S. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Interferons and cytokines. Shanghai Scientific & Technical Publishers. 2007.