8/ A huge thank you to @soumya-boston.bsky.social, @aliakbari.bsky.social, and members of the Raychaudhuri lab for their support and feedback. We are excited to see how genetic insights into the TCR will deepen our understanding of adaptive immunity and immune-mediated disease.

7/ While somatic recombination is an incredible engine to generate diversity in the repertoire, our findings suggest inherited variation in TCR genes is a parallel, complementary axis of diversity that may shape interindividual differences in immune responses.

6/ We then asked how inherited TCR variation shapes core aspects of T cell function. By genotyping TCR chains at single-cell resolution, we found TCR polymorphism alters thymic lineage commitment, influences T cell responses in diseased tissues, and modulates surface expression of the TCR complex.

5/ This was surprising — TCR genes are often thought to be interchangeable, yet our results suggest variation in a single gene was consequential enough to alter immune fitness in ancestral human populations.

4/ To understand how this class of genetic variation influences human immunity, we analyzed the TCR loci through the lens of natural selection. Interestingly, we found individual TCRα V and J genes showed signatures of balancing selection, while others carried signatures of positive selection.

3/ We also found substantial variation in the number of distinct functional V gene alleles individuals carry — some donors only had two-thirds as many as others, potentially shaping the breadth of the T cell responses they can generate.

2/ Using recent public long-read sequencing data from over 2600 donors, we built a nearly-complete map of common genetic variation in TCR genes. We discovered hundreds of new V and J gene alleles, and found population-level amino acid variation at almost every single position within Vα/β genes.

1/ T cell immunity relies on recognition of antigen-HLA complexes by T cell receptors. While polymorphism in HLA genes that perform antigen presentation has been widely studied, much less is known about inherited variation in the antigen recognition machinery — the V, D, and J genes encoding TCRs.

Excited to share our preprint studying the genetics of T cell receptors! bit.ly/tcrdiversity with @soumya-boston.bsky.social @broadinstitute.org 🧵