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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI107625-04
Application #
9114461
Study Section
Immunity and Host Defense (IHD)
Program Officer
Ramachandra, Lakshmi
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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
Quinn, Kylie M; Zaloumis, Sophie G; Cukalac, Tania et al. (2016) Heightened self-reactivity associated with selective survival, but not expansion, of naïve virus-specific CD8+ T cells in aged mice. Proc Natl Acad Sci U S A 113:1333-8

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