CD161highCD8+T cells bear pathogenetic potential in multiple sclerosis

Abstract

To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting-leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4(+) and CD8(+) T-cell subsets. Disease-related differences emerged only in the CD8(+) T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161(high)CD8(+) T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6(+), cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17(+)CD8(+) T cells. In the CD161(high)CD8(+) subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161(+)CD8(+)CD3(+) T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8(+) T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…Moreover, all the circulating Tc17 cells are contained within this CD161 high subset, further suggesting a role for this subset of CD8 T cells in MS pathogenesis [46]. It is at present unclear whether these CD161 high CD8 T cells are conventional HLA class I-restricted T cells or whether they belong to an innate-like T cell subset.…”

“…In contrast, inactive lesions contained only few IL-17-producing T cells [45]. Furthermore, Annibali et al have identified significant up-regulation of natural killer receptor protein 1a/CD161 and increased numbers of CD161 high CD8 T cells in the peripheral blood of MS patients [46]. This subset of CD8 T cells includes most of the CCR6+, effector memory T cells with pro-inflammatory properties.…”

“…The adoptive transfer of H-2D b -restricted CD8 T cells specific for the short MOG 37-46 peptide also induces EAE into C57Bl/6 recipients [58]. Therefore, MOG is thought to contain at least 2 nested encephalitogenic epitopes: MOG [40][41][42][43][44][45][46][47][48] that elicits a CD4 T cell response in the context of H-2I-A b [59], and MOG [37][38][39][40][41][42][43][44][45][46] inducing a CD8 T cell response restricted to H-2D b [58]. Most recently, MOG 42-50 was found to bind to H-2D b molecule to elicit a CD8 T cell responses in MOG-deficient animals.…”

“…PLP [45][46][47][48][49][50][51][52][53] immunization in complete Freund adjuvant induces mild disease in 71% of these mice, followed in 25% of them by a severe disease leading to hind limb paralysis. The PLP [45][46][47][48][49][50][51][52][53] -specific CD8 T cells mediate the first phase of this disease, whereas the second phase is due to CD4 T cells targeting the MOG epitope in the context of the murine I-A b molecule [66]. Therefore, this study demonstrates that CD8-driven autoimmune demyelination can initiate epitope spreading.…”

Innate‐like CD8+ T‐cells and NK cells: converging functions and phenotypes

“…Similarly, MAIT cells are also well established to be recruited to sites of inflammation,81, 125 and have been found to be enriched in the synovial fluid of patients with ankylosing spondylitis126 and RA127. They have also been shown to be recruited to the lung of patients with active tuberculosis infection,81, 82 increased in inflamed intestinal tissues in patients with inflammatory bowel disease,125 adipose tissues of obese patients,128 and are present in multiple sclerosis (MS) lesions 129, 130, 131. MAIT cell recruitment to inflamed tissues is further increased by their upregulation of chemokine receptors CXCR3, which binds IFN‐dependent ligands CXCL9/10/11 in inflamed tissues 118…”