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)
Type
Research Project (R01)
Project #
5R01AI107625-02
Application #
8709989
Study Section
Immunity and Host Defense (IHD)
Program Officer
Lapham, Cheryl K
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
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
Duan, Susu; Thomas, Paul G (2016) Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection. Front Immunol 7:25
Milasta, Sandra; Dillon, Christopher P; Sturm, Oliver E et al. (2016) Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function. Immunity 44:88-102
Greene, J M; Dash, P; Roy, S et al. (2016) MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. Mucosal Immunol :
Valkenburg, Sophie A; Josephs, Tracy M; Clemens, E Bridie et al. (2016) Molecular basis for universal HLA-A*0201-restricted CD8+ T-cell immunity against influenza viruses. Proc Natl Acad Sci U S A 113:4440-5
Guo, Xi-Zhi J; Dash, Pradyot; Calverley, Matthew et al. (2016) Rapid cloning, expression, and functional characterization of paired αβ and γδ T-cell receptor chains from single-cell analysis. Mol Ther Methods Clin Dev 3:15054
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
Cukalac, Tania; Kan, Wan-Ting; Dash, Pradyot et al. (2015) Paired TCRαβ analysis of virus-specific CD8(+) T cells exposes diversity in a previously defined 'narrow' repertoire. Immunol Cell Biol 93:804-14
Dash, Pradyot; Wang, George C; Thomas, Paul G (2015) Single-Cell Analysis of T-Cell Receptor αβ Repertoire. Methods Mol Biol 1343:181-97
Furman, David; Jojic, Vladimir; Sharma, Shalini et al. (2015) Cytomegalovirus infection enhances the immune response to influenza. Sci Transl Med 7:281ra43

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