ABSTRACTPolymorphisms in thehuman leukocyte antigen(HLA) genes within themajor histocompatibility complex(MHC) locus strongly influence autoimmune disease risk1–5. Two non-exclusive hypotheses exist about the pathogenic role ofHLAalleles; i) the central hypothesis, whereHLArisk alleles influence thymic selection so that the probability of T cell receptors (TCRs) reactive to pathogenic antigens is increased6–8; and ii) the peripheral hypothesis, whereHLArisk alleles increase the affinity for pathogenic antigens9–11. The peripheral hypothesis has been the main research focus in autoimmunity, while human data on the central hypothesis are lacking. Here, we investigated the influence ofHLAalleles on TCR composition at the highly diverse complementarity determining region 3 (CDR3), where TCR recognizes antigens. We demonstrated unexpectedly powerfulHLA-CDR3 associations. The strongest association was found atHLA-DRB1amino acid position 13 (n = 628 subjects, explained variance = 9.4%;P= 4.1 x 10−138). This HLA position mediates genetic risk for multiple autoimmune diseases. In structural analysis of TCR-peptide-MHC complexes, we observed that HLA-DRB1 position 13 does not interact directly with CDR3, but is proximate to antigenic peptide residues that are also close to CDR3. We identified multiple CDR3 amino acid features enriched byHLArisk alleles; for example, the risk alleles of rheumatoid arthritis, type 1 diabetes, and celiac disease all increase the hydrophobicity of CDR3 position 109 (P< 2.1 x 10−5). In the setting of celiac disease, the CDR3 features favored byHLArisk alleles are more enriched among candidate pathogenic TCRs than control TCRs (P= 2.4 × 10−6for gliadin specific TCRs). Together, these results provide novel genetic evidence supporting the central hypothesis.