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
Woodruff, Matthew C; Heesters, Balthasar A; Herndon, Caroline N et al. (2014) Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J Exp Med 211:1611-21
Cukalac, Tania; Chadderton, Jesseka; Handel, Andreas et al. (2014) Reproducible selection of high avidity CD8+ T-cell clones following secondary acute virus infection. Proc Natl Acad Sci U S A 111:1485-90
Bettini, Matthew L; Guy, Clifford; Dash, Pradyot et al. (2014) Membrane association of the CD3? signaling domain is required for optimal T cell development and function. J Immunol 193:258-67