The T cell receptor (TCR) recognizes antigen in the context of a major histocompatibility (MHC) molecule, which is critical for determining T cell fate during thymic development as well as peripheral activation, differentiation and memory development. As a mechanosensor, the TCR complex interprets the information embedded in the peptide-MHC and transduces it from the ligand-binding interface across the TCR ?? chains to the associated CD3 subunits into biochemical signals in the form of binding/unbinding of kinase/ phosphatase molecules and their enzymatic reactions. During an acute resolving infection such as LCMV Arm in mice, nave CD8+ T cells will proliferate and expand during the first week of infection. This expansion is antigen-specific and dependent on help from panoply of co-stimulatory and inflammatory cytokines. If successful and the virus is cleared, the majority of these cells will die by apoptosis during the contraction phase that lasts typically between 8-30 days post infection. A small portion of these effector cells will then differentiate to memory T cells where they can be poised to respond to a recall antigen quicker and with more vigor than during the primary response. Since tissue-resident immune cells are known to be phenotypically and functionally different from cells circulating in the blood, discrimination of cells that particpate in local immune responses and those that are circulating in the vasculature is of great interest. In this study, we hypothesize that the anatomic compartmentalization of anti-viral CD8+ T cells affect TCR-pMHC interaction and functional differentiation of T cells during the immune contraction phase. This hypothesis is based on our recent analysis of effective 2D TCR affinity, measured in situ by highly sensitive two-dimensional (2D) methods. Anti-viral CD8+ T cell responses reach a peak between 7-8 days post infection with subsequent elimination of viral titers by day 8. Surprisingly, the 2D TCR affinity of genetically identical P14 TCR on T cells in the splenic red pulp was increased ~5 fold as compared to that of the WP T cells on days 9 and 11 after the cessation of anti-viral immune responses. These data suggest that differentially localized anti-viral CD8+ T cells receive disparate signals from distinct microenvironments, thus potentially affecting their function and differentiation. In this proposal, we aim to understand ho anatomic localization of anti-viral CD8+ T cells regulates TCR-pMHC interaction and potentially influence the fate of antigen-specific T cells. Immune cells continuously circulate to patrol the body searching for invading pathogens. Upon infection, many immune cells are locally accumulated into the site of infection to more efficiently clear the pathogen and prevent the spread of infection. The specific location of these immune cells, whether they are resident in the white pulp or red pulp may have important implication for how strongly they react to the pathogen, preferentially expand, die or become long lasting memory cells poised to respond to a recall antigen quicker and with more vigor than during the primary response. These differentially localized immune cells may receive disparate signals from distinct microenvironments, thus potentially affecting their function and differentiation.

Public Health Relevance

We hypothesize that induction of liver fibrosis and disease is dependent upon the early activation and dysfunction of intrahepatic B lymphocytes and moreover, a novel subset of T helper cells can affect the balance of B cell tolerance and autoimmunity during chronic liver disease. We believe that our studies will provide immunological basis for a number of future broadly targeting therapeutics with the ability to reverse the progression and sequelae of chronic liver disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Kelly, Halonna R
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Tedesco, Dana; Thapa, Manoj; Chin, Chui Yoke et al. (2018) Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic ?? T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease. Gastroenterology 154:2178-2193
Saggu, Gurpanna; Okubo, Koshu; Chen, Yunfeng et al. (2018) Cis interaction between sialylated Fc?RIIA and the ?I-domain of Mac-1 limits antibody-mediated neutrophil recruitment. Nat Commun 9:5058
Tedesco, Dana; Grakoui, Arash (2018) Environmental peer pressure: CD4+ T cell help in tolerance and transplantation. Liver Transpl 24:89-97
Aguilar-Valenzuela, Renan; Netland, Jason; Seo, Young-Jin et al. (2018) Dynamics of Tissue-Specific CD8+ T Cell Responses during West Nile Virus Infection. J Virol 92:
Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev et al. (2017) CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease. Hepatology 65:661-677
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Ju, Lining; Chen, Yunfeng; Li, Kaitao et al. (2017) Dual Biomembrane Force Probe enables single-cell mechanical analysis of signal crosstalk between multiple molecular species. Sci Rep 7:14185
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Boisvert, Maude; Zhang, Wanrui; Elrod, Elizabeth J et al. (2016) Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells. J Immunol 197:4848-4858
Cole, David K; Bulek, Anna M; Dolton, Garry et al. (2016) Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J Clin Invest 126:2191-204

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