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
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