Activation of myelin reactive T cells in multiple sclerosis: A possible role for T cell degeneracy?

Abstract

While it is widely accepted that myelin reactive T cells are key players in the immunopathogenesis of multiple sclerosis (MS), the initial triggers that turn on these self-reactive T-cells remain to be determined. One mechanism, which is already text book knowledge for a decade, is molecular mimicry by which viral or microbial antigens are able to cross-activate T cells specific for myelin epitopes, the major target in MS pathology. Although proof of concept for this principle was given in animal model studies, evidence for such a mechanism in MS is limited. In this issue, Zhang et al. demonstrate an increased frequency of T cells that cross-react with a wide variety of antigens, a phenomenon termed as T cell degeneracy. While the role of these degenerate T cells in MS remains to be determined the authors now provide new elegant tools to study this T cell population, thus providing a starting point to better understand their function in MS.

Recognition of viral and self-antigens by T H 1 and T H 1/T H 17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses

“…29 Molecular mimicry was proposed as a possible mechanism because some EBV-specific T cells with a degenerate T-cell receptor (TCR) cross-react with myelin antigens. [30][31][32] Nevertheless, a single virus that causes MS was not identified, and the role of viral infections in patients with MS remains enigmatic and debated. [27][28][29] We report here that autoreactive T H 1/T H 17 CM cells expand in peripheral blood of patients with RR-MS and accumulate in the CSF on attacks together with virus-specific T H 1 cells, suggesting that these 2 subsets have distinct roles in relapses and immune surveillance.…”

The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance?

“…Nevertheless, myelinderived antigens are probably not the only relevant self-antigens in MS. In particular, pathogenic T cells in MS may have a degenerate T cell receptor (TCR) that cross-reacts with several structurally related self-peptides, or potentially even directly with the backbone of some MHC molecules [34][35][36][37]. These autoreactive T cells have a high pathogenic potential because they could be activated by any antigen-presenting cell (APC) that expresses MHC class II and costimulatory molecules.…”

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

“…Recovered immune cells show a bias towards a tolerogenic phenotype with elevated numbers of regulatory T lymphocytes, a shift towards Th2 responses, increased levels of immunoregulatory cytokines [transforming growth factor-β, interleukin (IL)-10] and lower levels of Th1 and Th17 cytokines (IFN-γ, IL-12, and IL-17) and higher expression levels of co-inhibitory receptor molecues (programmed cell death protein 1, lymphocyte-activation gene 3) on T lymphocytes [63,64]. Autoreactive T-cell clones were reduced after immune cell reconstitution and T cells displayed an increased T-cell receptor (TCR) diversity [61,65]. The migratory capacity of T cells was shown to be reduced after alemtuzumab treatment, leading to a lower migration of T cells into the CNS.…”