Linking T cell receptor sequence to T cell function

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T cells are critical effector cells of the adaptive immune system which recognize foreign antigen in the form of peptides presented by host cell major histocompatibility complexes (MHC). Each T cell bears a unique antigen recognition receptor, the T cell receptor (TCR), which determines the exquisite specificity and the affinity with which an individual T cell binds peptide-MHC. The TCR is generated through rearrangement of germline encoded gene segments and the addition of non-templated (non-germline encoded) nucleotides by an enzyme called terminal deoxynucleotidyl transferase (TdT). The interaction strength between the TCR and peptide-MHC is a critical parameter in all T cell fate decisions, from selection in the thymus during development to differentiation during infection. Yet, due to the enormous diversity of TCRs that can be made (>1015 distinct receptors), predicting functional characteristics of a T cell from its TCR sequence is an unsolved challenge. Moreover, while the enormous TCR diversity within a T cell repertoire that is added by TdT during TCR gene segment rearrangement is thought to be essential in effective host protection, this has not been demonstrated experimentally. Thus, the link between TCR sequence diversity, pMHC binding strength, and T cell function in host protection remains unclear. To date, it has been difficult to discern global patterns in TCR sequence or binding affinity for a T cell population without prior knowledge of the range of peptide-MHC ligands for each TCR. To overcome this limitation, we propose a novel approach that interrogates the impact of the TCR sequence on T cell function in an unbiased manner. We previously described that T cell expression of the membrane protein CD5 is directly proportional to the strength of the TCR signal obtained from self-ligands as well as foreign antigens presented in the context of MHC. Thus, by sorting CD4 T cells into CD5hi and CD5lo populations, we can now investigate properties of TCR sequences with distinct binding strengths for peptide-MHC without requiring prior knowledge of the peptides that they recognize. We hypothesize that CD5hi cells contain predominantly germline-encoded TCRs that are evolutionarily conserved to bind foreign peptide-MHC that we frequently encounter as a species. In contrast, we predict that CD5lo cells are enriched for TdT-dependent TCRs to provide the additional diversity that is required to respond to new and divergent pathogens. We will determine whether lower affinity TCRs that are generated by TdT-mediated junctional nucleotide additions play a fundamentally different role in the immune system than do high affinity TCRs. Overall, my research program will provide fundamental insight into the quantitative and qualitative features of an effective T cell repertoire and shed light on the evolutionary pressures that led to the use of TdT to increase TCR diversity.