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 #
1R01AI107625-01
Application #
8573498
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$450,423
Indirect Cost
$181,388
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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
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
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
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
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
Duan, Susu; Thomas, Paul G (2016) Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection. Front Immunol 7:25
Kohlhapp, Frederick J; Huelsmann, Erica J; Lacek, Andrew T et al. (2016) Non-oncogenic Acute Viral Infections Disrupt Anti-cancer Responses and Lead to Accelerated Cancer-Specific Host Death. Cell Rep 17:957-965
Guo, Xi-Zhi J; Dash, Pradyot; Calverley, Matthew et al. (2016) Rapid cloning, expression, and functional characterization of paired ?? and ?? T-cell receptor chains from single-cell analysis. Mol Ther Methods Clin Dev 3:15054
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
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

Showing the most recent 10 out of 22 publications