Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated…

Abstract

Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.

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BibTeX RIS

BibTeX

@misc{risch2026refinement,
  title = {{Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity}},
  author = {I. Risch and Q. Wu and R. Devkota and S. Y. Li and J. Um and T. Alves Pereira Neto and S. Walden and P. H. Arantes de Faria and A. Belean and L. Durham and M. Tang and Z. Qaiyum and R. D. Inman and L. S. Taams and X. Yang and P. A. Mudd and N. Borcherding and M. Griffith and O. L. Griffith and M. A. Paley},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.18.752092},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752092v1},
  note = {CC BY-NC},
}

RIS

TY  - UNPB
TI  - Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity
AU  - I. Risch
AU  - Q. Wu
AU  - R. Devkota
AU  - S. Y. Li
AU  - J. Um
AU  - T. Alves Pereira Neto
AU  - S. Walden
AU  - P. H. Arantes de Faria
AU  - A. Belean
AU  - L. Durham
AU  - M. Tang
AU  - Z. Qaiyum
AU  - R. D. Inman
AU  - L. S. Taams
AU  - X. Yang
AU  - P. A. Mudd
AU  - N. Borcherding
AU  - M. Griffith
AU  - O. L. Griffith
AU  - M. A. Paley
PY  - 2026
DA  - 2026/09/18
PB  - bioRxiv
DO  - 10.64898/2026.09.18.752092
UR  - https://www.biorxiv.org/content/10.64898/2026.09.18.752092v1
AB  - Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.
ER  -

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