Small numbers of T cells specific to different myelin-antigens cooperate to induce autoimmunity in a murine model of multiple sclerosis

Abstract

Abstract T cells play a crucial role in many autoimmune diseases including multiple sclerosis (MS). Despite this, mechanisms of peripheral tolerance and dysregulation of these mechanisms during autoimmunity remain elusive. Myelin-reactive T cells are present in the blood of both healthy controls and patients with MS and T cells from patients with MS react to many different myelin peptides. The strongest genetic risk factor for developing MS is the HLA-DRB1*1501 haplotype, indicating that peptide binding to this MHC aids in disease induction. It is unlikely and not supported by current human studies that patients exhibit large populations of T cells specific for a single myelin-antigen. In contrast, a quorum of 2–5 low avidity autoreactive T cells specific for one epitope might suffice to induce autoimmunity. We hypothesized that a quorum could be established and induce autoimmunity by small numbers of antigen-specific T cells recognizing different myelin antigen peptides, particularly in genetically susceptible individuals. We utilized wild-type C57BL/6 mice and transgenic mice expressing the human MHC HLA-DRB1*1501 allele to assess the effect of inducing experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis, with low numbers of different myelin peptide-specific T cells or myelin peptides at suboptimal doses. In this proof-of-principle study, we found that EAE can be initiated by the cooperation of small numbers of myelin peptide-specific T cells reactive against different myelin epitopes. The results support the hypothesis that a quorum of T cells could be reached by multiple antigen-specific T cells and could suffice to initiate autoimmune disease.