In contrast to B cells, the T cell receptor repertoire is generally considered fixed once fully mature T cells exit the thymus. We recently developed the technology to detect and sequence the message of paired ?? T cell receptors from single cells in mice and humans. This approach permitted two important observations: 1) the proportion of cells transcribing message for two Tcra chains varies dramatically over the course of acute and memory immune responses and 2) clonal lineages of T cells in vivo demonstrate evidence of receptor revision in the periphery. Using innovative in vitro single cell culture platforms, unique in vivo models including conditional RAG-deficient mice, and a valuable panel of longitudinal human samples, we propose to extend these observations to assess the hypothesis that optimal T cell responses to viral infections require an inherently plastic peripheral repertoire. Our three aims test the specific hypotheses that 1) Dual TCR? allele expression regulates TCR signal strength and functional T cell activity by interfering with in frame allele transcription and/or TCR:CD3 assembly, 2) Peripheral TCR revision is induced in most na?ve T cells by strong TCR signaling and 3) Both dual allele expression and revision are required for optimal T cell activity in acute and chronic infections (influenza and mCMV). These studies combine a suite of novel in vitro technology and in vivo models that will result in a new understanding of how optimal antiviral T cell responses are generated and regulated, with broad implications for our understanding of adaptive immunity.
These studies combine a suite of novel in vitro technology and in vivo models that will result in a new understanding of how optimal antiviral T cell responses are generated and regulated, with broad implications for our understanding of adaptive immunity. We propose that two novel regulatory mechanisms-dual allele expression and revision-play an important role in the development and maintenance of effective T cell immunity to viral challenge. We will test our central hypothesis that optimal T cell responses in virus infections require an inherently plastic peripheral repertoire.
|Souquette, Aisha; Thomas, Paul G (2018) Past Life and Future Effects-How Heterologous Infections Alter Immunity to Influenza Viruses. Front Immunol 9:1071|
|Schattgen, Stefan A; Thomas, Paul G (2018) Bohemian T cell receptors: sketching the repertoires of unconventional lymphocytes. Immunol Rev 284:79-90|
|Zamora, Anthony E; Crawford, Jeremy Chase; Thomas, Paul G (2018) Hitting the Target: How T Cells Detect and Eliminate Tumors. J Immunol 200:392-399|
|Yang, Kai; Blanco, Daniel Bastardo; Chen, Xiang et al. (2018) Metabolic signaling directs the reciprocal lineage decisions of ?? and ?? T cells. Sci Immunol 3:|
|Nguyen, Thi Ho; Bird, Nicola L; Grant, Emma J et al. (2017) Maintenance of the EBV-specific CD8+ TCR?? repertoire in immunosuppressed lung transplant recipients. Immunol Cell Biol 95:77-86|
|Greene, J M; Dash, P; Roy, S et al. (2017) MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. Mucosal Immunol 10:802-813|
|Lee, Edward S; Thomas, Paul G; Mold, Jeff E et al. (2017) Identifying T Cell Receptors from High-Throughput Sequencing: Dealing with Promiscuity in TCR? and TCR? Pairing. PLoS Comput Biol 13:e1005313|
|Dash, Pradyot; Fiore-Gartland, Andrew J; Hertz, Tomer et al. (2017) Quantifiable predictive features define epitope-specific T cell receptor repertoires. Nature 547:89-93|
|Ghoneim, Hazem E; Fan, Yiping; Moustaki, Ardiana et al. (2017) De Novo Epigenetic Programs Inhibit PD-1 Blockade-Mediated T Cell Rejuvenation. Cell 170:142-157.e19|
|Ghoneim, Hazem E; Zamora, Anthony E; Thomas, Paul G et al. (2016) Cell-Intrinsic Barriers of T Cell-Based Immunotherapy. Trends Mol Med 22:1000-1011|
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