Characterization of CD8+ T cell repertoire in identical twins discordant and concordant for multiple sclerosis

Abstract

Autoreactive CD4+ and CD8+ T cells directed against CNS autoantigens may play a role in the development of multiple sclerosis (MS). Identical twins share the same genetic background but not the TCR repertoire that is shaped by the encounter with self or foreign antigens. To gain insights into the interplay between MS and T cell repertoire, peripheral blood CD4+ and CD8+ T lymphocytes and their CCR7+/CCR7- subsets from five pairs of identical twins (four discordant and one concordant for MS; none of which had taken disease-modifying therapy) were compared by TCR beta-chain (TCRB) complementary-determining region 3 (CDR3) spectratyping. CD4+ T cells generally showed a Gaussian distribution, whereas CD8+ T cells exhibited subject-specific, widely skewed TCR spectratypes. There was no correlation between CD8+ T cell oligoclonality and disease. Sequencing of predominant spectratype expansions revealed shared TCRB-CDR3 motifs when comparing inter- and/or intrapair twin members. In many cases, these sequences were homologous to published TCRs, specific for viruses implicated in MS pathogenesis, CNS autoantigens, or copaxone [glatiramer acetate (GA)], implying the occurrence of naturally GA-responding CD8+ T cells. It is notable that these expanded T cell clones with putative pathogenic or regulatory properties were present in the affected as well as in the healthy subject, thus suggesting the existence of a "MS predisposing trait" shared by co-twins discordant for MS.

Genetic and Molecular Approaches to the Immunopathogenesis of Multiple Sclerosis: An Update

“…MZ twins are therefore not genetically identical at these loci, which could explain the low concordance of MS and other immune mediated diseases among MZ twins [183]. In accordance with this hypothesis, CDR3 spectratyping of TCRs showed significantly different patterns between affected and the unaffected MZ twins [184,185]. Moreover, T cells from MZ twins concordant for MS used similar TCR V genes in response to both an autoantigen (MBP) and a foreign antigen (tetanus toxoid), whereas T cells from discordant MZ twins used different TCR V genes [186].…”

Clonal composition of neuroantigen-specific CD8+ and CD4+ T-cells in multiple sclerosis

“…These findings correlate with a previous study finding little or no difference in the clonal composition of myelin antigen-reactive T-cells between MS patients and healthy subjects (Hafler et al, 1996). Possibly a more detailed breakdown of the CD8+ T-cell population would provide more insights, such as one performed by Somma et al, where they found a skewed repertoire in 3 pairs of MS discordant twins when they divided the CD8+ T-cell fraction into CCR7 negative (effector memory) and CCR7 positive (central memory, naïve) fractions (Somma et al, 2007). …”

Enumeration of human antigen–specific naive CD8+ T cells reveals conserved precursor frequencies

“…One thing is clear, even in identical twins possessing the same genetic information, the T-cell repertoires are distinct and in some cases may account for discordance in the development of diseases such as type 1 diabetes or multiple sclerosis. [8][9][10] Standard quantitative assays for measuring specific CD8 ϩ T-cell responses, such as pMHCI-labeled tetramer, intracellular cytokine staining, and enzyme-linked immunospot (ELISPOT), have a limit of detection of 5 ϫ 10 Ϫ5 . Moreover, the latter 2 assays monitor functional activity and thus are not adequate for studying naive antigen-specific CD8 ϩ T cells.…”