Molecular mechanisms of cytokine-induced modulation of T cell antigen receptor responsiveness

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The overall objective of this research program is to understand how inflammatory cytokines produced during innate immune responses impact on the adaptive immune responses of cytotoxic T lymphocytes. Cytokine responses are regulated by `suppressors of cytokine signaling' (SOCS) family proteins. While studying the deregulated homeostasis of the T cell compartment in mice lacking SOCS1, we made a fortuitous observation: SOCS1-deficient CD8 T cells proliferate robustly in response to cytokines that regulate T cell homeostasis and this is amplified by inflammatory cytokines; while this was not unexpected, CD8 T cells from control mice also proliferated in response to synergistic stimulation by inflammatory and homeostatic cytokines. The latter was unexpected because normal T cells require two signals - one via the antigen receptor and the other via a costimulatory receptor. As both inflammatory and homeostatic cytokines can become available during inflammatory conditions (in response to infections or sterile inflammation), we started investigating the physiological significance and pathological consequences of such antigen- and co-stimulation- independent activation of naïve T cells. Over the past decade, we have shown that (i) the cytokine-stimulated T cells acquire increased sensitivity to antigens as they respond to limiting amounts of antigens and weakly agonistic antigenic peptides, (ii) such antigen non-specific stimulation can activate autoreactive T cells in vivo, and (iii) this process is regulated by SOCS1. We have also found that the `cytokine-primed' T cells display increased metabolic fitness and marked changes in their plasma membrane that could impact T cell antigen receptor (TCR) signaling. In the proposed research, we aim to understand the mechanistic and molecular basis of the increased antigen responsiveness of cytokine-primed T cells. As our candidate approaches have shown very limited scope, we propose to use unbiased genomic (ATACseq, RNAseq) and proteomic (iTRAQ differential proteomics) approaches to gain a comprehensive view of the molecular changes that occur during cytokine priming. The selected candidate genes/proteins/pathways will be tested for their contribution to cytokine priming using in vitro assays and in vivo models. The proposed research program will put emphasis on training students in cutting-edge technologies of genomics and proteomics, and bioinformatics analyses. In addition they will be trained in several immunology techniques related to animal handling, T cell biology, flow cytometry, confocal microscopy, molecular biology techniques and bioinformatics analyses. The trainees will gain knowledge and skill set suitable for both academic career and industry jobs. The outcome of this research will impact on how cytokines could be exploited for boosting immune responses, and how their signaling pathways could be targeted to control aberrant immune responses.