Background/Purpose: Behçet’s disease (BD) is an HLA class I-associated disorder, given its strong link to HLA-B*51. However, evidence of HLA class I restriction is lacking, and candidate antigens are elusive. Here, we hypothesized that clonal CD8 T cell expansions are present in BD at tissue sites during active disease aiming to provide evidence of HLA class I restriction by identifying their disease-related CD8 TCR.

Methods: We performed scRNAseq with TCR V(D)J analyses in PBMC from a Turkish cohort of 37 untreated subjects (14 HD, 23 BD) with ocular and vascular BD. In a separate set of experiments, we obtained anterior chamber fluid cells from two additional HLA-B*51⁺ Behçet’s uveitis (BU) subjects from an independent cohort, as well as time-matched autologous peripheral blood, assessed TCR sequences, clonotype- and T cell phenotype distribution between peripheral blood and the eye, and clonotype sharing across study subjects in both cohorts.

Results: Anterior chamber fluid cells in BU showed substantial oligoclonal CD8 T cell expansions. Highly expanded ocular clonotypes overlapped with autologous peripheral blood exhibiting an intraclonotype shift towards a more cytotoxic (Granzyme B⁺) phenotype in the eye over peripheral blood. An identical disease-related CD8 a/bTCR, determined in the eye-blood paired sample experiments, was re-identified in HLA-B*51⁺ active uveitis peripheral blood in the Turkish cohort but not in HDs or BD subjects without uveitis. We identified additional clonotypes which showed high CDR3 sequence similarity to our experimentally determined TCR computationally, using TCRdist. Again, we re-located those in HLA-B*51⁺ subjects with active uveitis but not in HD, BD without uveitis, or HLA-B*51^– subjects.

Conclusion: We demonstrate the presence of highly expanded CD8 T cells in BU eyes and autologous peripheral blood and identify disease-associated TCR across independent cohorts of affected HLA-B*51-carrying subjects but not HDs. Our findings suggest that an HLA class I-restricted process drives BD in a subset of clinically distinct patients and will facilitate antigen discovery by enabling the identification of cognate peptides in an HLA-B*51 restriction context.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/behcets-disease-associated-tcr-in-the-eye-points-to-hla-class-i-restricted-autoimmunity/