Role of TCR affinity in function, proliferation, memory generation, and exhaustion during human viral infection




Williams, Chad Manjeot

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TCR affinity is a strong predictor of T cell function, proliferation, exhaustion, and generation of immune memory. 2D TCR affinity quantification is derived from direct antigen interaction on the T cell itself, making it a more physiologically relevant form of TCR affinity information. 2D TCR affinity demonstrated a 1000-fold affinity range within in vitro cultured Naïve Hepatitis C Virus (HCV) specific CD8⁺ T cells from HCV negative individuals. 2D affinity predicted T cell function better than other affinity measurement techniques, and identified TCRs capable of a CD8 independent functional response. High affinity HCV TCRs were more sensitive to low concentrations of antigen presentation giving these TCRs a greater capacity for immune surveillance during infection. However, the interrogation of the role TCR affinity plays in the immune response of CD8⁺ T cells during an ongoing viral infection has yet to be realized. With the advent of high throughput TCR affinity quantification techniques like in situ TCR affinity and sequence test (iTAST), it is now possible for rapid ex vivo isolation and TCR affinity quantification of antigen specific T cells responding to an ongoing viral infection. iTAST was used to isolate naïve, effector, and memory subsets of Cytomegalovirus (CMV) specific CD8⁺ T cells in the blood and spleen of CMV infected individuals. 2D TCR affinity of naïve cells had 1000-fold affinity range, yet effector and memory subsets were highly enriched for cells expressing medium affinity TCRs in comparison to either high or low affinity counterparts. This was corroborated by TCR sequencing analysis of the same populations for which 2D TCR affinity distributions were characterized. Surprisingly, the functional response of medium affinity TCRs, despite more reliance on CD8, was similar to that of TCRs with an order of magnitude higher TCR affinity, and seemed to be linked to intrinsic differences in inhibitory marker regulation and expression of PD-1, Tim-3, and LAG-3. Additionally, medium affinity CMV TCRs gave CD8⁺ T cells a proliferative advantage during in vitro culture conditions. In summary, TCR affinity influences CD8⁺ T cell function, proliferation, and exhaustion thus helping maintain immunological memory within an ongoing human viral infection


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