Autoimmunity-Associated T Cell Receptors Recognize HLA-Variant-Bound Peptides

The immune response in autoimmune disease recapitulates that of responses directed against infection, except that self-antigens are, or become, the target of the adaptive immune system. These self-antigens may drive a process that is localized within a specific organ, such as the thyroid gland (Grave’s disease, Hashimoto’s thyroiditis) or brain (multiple sclerosis).

Autoimmune disease occurs when an immune response attacks one’s own tissues. Like all adaptive immune responses, it is focused on specific antigens by T-cell receptors and B-cell receptors. In contrast to infection, the antigens that these cells recognize are processed from proteins within the target organ and this drives a chronic inflammatory process that disrupts the normal function of the tissue.

A large international team of immunologists partially led by those at Washington University School of Medicine in St. Louis (St Louis, MO, USA) investigated the theory that some T cells that react to microbes also may react to normal human proteins, causing autoimmune disease. The autoimmune diseases ankylosing spondylitis, which involves arthritis in the spine and pelvis, and acute anterior uveitis, which is characterized by inflammation in the eye, are both strongly associated with an HLA variant called HLA-B*27.

The team devised a method to identify protein fragments that drive a T cell response when combined with HLA-B*27, and mapped the fragments against the human genome and five bacterial genomes to identify proteins from which the fragments may have originated. They isolated orphan T cell receptors (TCRs) expressing a disease-associated public β-chain variable region–complementary-determining region 3β (BV9–CDR3β) motif2,3,4 from blood and synovial fluid T cells from individuals with ankylosing spondylitis (AS) and from the eye in individuals with acute anterior uveitis (AAU).

These TCRs showed consistent α-chain variable region (AV21) chain pairing and were clonally expanded in the joint and eye. The investigators used HLA-B*27:05 yeast display peptide libraries to identify shared self-peptides and microbial peptides that activated the AS- and AAU-derived TCRs. Structural analysis revealed that TCR cross-reactivity for peptide–MHC was rooted in a shared binding motif present in both self-antigens and microbial antigens that engages the BV9–CDR3β TCRs.

Michael Paley, MD, PhD, an Assistant Professor of Medicine and a co-author of the study, said, “For ankylosing spondylitis, the average time between initial symptoms and actual diagnosis is seven to eight years. Shortening that time with improved diagnostics could make a dramatic impact on patients' lives, because treatment could be initiated earlier. As for therapeutics, if we could target these disease-causing T cells for elimination, we could potentially cure a patient or maybe even prevent the disease in people with the high-risk genetic variant. There's a lot of potential for clinical benefit here.” The study was published on December 7, 2022 in the journal Nature.

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