CD8+ T cells are critical components of the adaptive immune response important for controlling viral infections. The affinity of T cell receptor for antigen triggers the activation of CD8+ T cells and drives the extent of the anti-viral response. Despite the key role of affinity in T cell activation, we still know quite little about the dynamic of antigen recognition in terms of the breadth of affinities and potential changes in affinity as the immune response evolves from initial triggering stage through memory. In addition, we lack data on differences in T cell affinities during acute infections, which elicit effective immune responses, and chronic infections where cellular immunity proves ineffective. The importance of TCR affinity for antigen recognition and our lack of knowledge are compelling reasons to investigate this issue. Toward these goals, we propose to use the micropipette adhesion assay to rigorously define the breadth of CD8+ T cell affinities in 2 dimensions (2D) during acute, chronic, and epitope loss viral infections. Recent work has highlighted the importance of 2D kinetic measurements to obtain an accurate view of T cell and APC interactions. While our proposal is focused toward the LCMV animal model to demonstrate proof of concept and define the role of affinity, the techniques could be readily transferred to patient samples to assess T cell affinity and CD8+ T cell precursor frequency during chronic infections such as HIV and HCV for which peptide antigens and HLA restriction molecules have been identified. The proposed experiments will increase our knowledge of T cell biology during chronic immune responses, with application to any situation in which T cells participate in the pathology. To test the stated hypotheses as to the breadth of the CD8+ anti-viral T cell response, we propose the following three specific aims:
Aim 1 - Determine the affinity profile of CD8+ T cells undergoing acute or chronic viral infections.
Aim 2 - Define the affinity profile and the parameters of diminished fitness of CD8+ T cells challenged by viral escape mutants.
Aim 3 - Characterize the affinity profile of CD8+ T cells after therapeutic interventions.

Public Health Relevance

CD8+ T cells play a major role in the anti-viral immune response. The overall goal of this grant is to define the range of polyclonal T cell affinities for viral antigens during acute and chronic infections. The proposed studies apply a novel means for assessing affinity to the LCMV animal model, but our results should be equally translatable to human chronic infections such as HIV and HCV. Therefore, our findings are highly relevant to human health and will prove to be a valuable asset for assessing disease prognosis and for the development of effective treatments.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-BDCN-W (03))
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Lapham, Cheryl K
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Emory University
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Sibener, Leah V; Fernandes, Ricardo A; Kolawole, Elizabeth M et al. (2018) Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding. Cell 174:672-687.e27
Kolawole, Elizabeth M; Andargachew, Rakieb; Liu, Baoyu et al. (2018) 2D Kinetic Analysis of TCR and CD8 Coreceptor for LCMV GP33 Epitopes. Front Immunol 9:2348
Sanecka, Anna; Yoshida, Nagisa; Kolawole, Elizabeth Motunrayo et al. (2018) T Cell Receptor-Major Histocompatibility Complex Interaction Strength Defines Trafficking and CD103+ Memory Status of CD8 T Cells in the Brain. Front Immunol 9:1290
Moore, Tamson; Wagner, Courtney Regan; Scurti, Gina M et al. (2018) Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells. Cancer Immunol Immunother 67:311-325
Andargachew, Rakieb; Martinez, Ryan J; Kolawole, Elizabeth M et al. (2018) CD4 T Cell Affinity Diversity Is Equally Maintained during Acute and Chronic Infection. J Immunol 201:19-30
Cole, David K; Fuller, Anna; Dolton, Garry et al. (2017) Dual Molecular Mechanisms Govern Escape at Immunodominant HLA A2-Restricted HIV Epitope. Front Immunol 8:1503
Baker, Brian M; Evavold, Brian D (2017) MHC Bias by T Cell Receptors: Genetic Evidence for MHC and TCR Coevolution. Trends Immunol 38:2-4
Liu, Yang; Blanchfield, Lori; Ma, Victor Pui-Yan et al. (2016) DNA-based nanoparticle tension sensors reveal that T-cell receptors transmit defined pN forces to their antigens for enhanced fidelity. Proc Natl Acad Sci U S A 113:5610-5
Shorter, Shayla K; Schnell, Frederick J; McMaster, Sean R et al. (2016) Viral Escape Mutant Epitope Maintains TCR Affinity for Antigen yet Curtails CD8 T Cell Responses. PLoS One 11:e0149582
Ma, Victor Pui-Yan; Liu, Yang; Blanchfield, Lori et al. (2016) Ratiometric Tension Probes for Mapping Receptor Forces and Clustering at Intermembrane Junctions. Nano Lett 16:4552-9

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