Cytotoxic NKG2C+ CD4 T Cells Target Oligodendrocytes in Multiple Sclerosis

Abstract

The mechanisms whereby immune cells infiltrating the CNS in multiple sclerosis patients contribute to tissue injury remain to be defined. CD4 T cells are key players of this inflammatory response. Myelin-specific CD4 T cells expressing CD56, a surrogate marker of NK cells, were shown to be cytotoxic to human oligodendrocytes. Our aim was to identify NK-associated molecules expressed by human CD4 T cells that confer this oligodendrocyte-directed cytotoxicity. We observed that myelin-reactive CD4 T cell lines, as well as short-term PHA-activated CD4 T cells, can express NKG2C, the activating receptor interacting with HLA-E, a nonclassical MHC class I molecule. These cells coexpress CD56 and NKG2D, have elevated levels of cytotoxic molecules FasL, granzyme B, and perforin compared with their NKG2C-negative counterparts, and mediate significant in vitro cytotoxicity toward human oligodendrocytes, which upregulated HLA-E upon inflammatory cytokine treatment. A significantly elevated proportion of ex vivo peripheral blood CD4 T cells, but not CD8 T cells or NK cells, from multiple sclerosis patients express NKG2C compared with controls. In addition, immunohistochemical analyses showed that multiple sclerosis brain tissues display HLA-E+ oligodendrocytes and NKG2C+ CD4 T cells. Our results implicate a novel mechanism through which infiltrating CD4 T cells contribute to tissue injury in multiple sclerosis.

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

“…12, 45) show that LCV-infected B cells have a central pathogenic role in the activation of highly pathogenic MHC-E-restricted effector memory cytotoxic T cells that, upon activation with the MOG34-56 peptide (core epitope [40][41][42][43][44][45][46][47][48], can elicit MS-like pathology and disease. Notably, similar autoaggressive CTLs were found in MS lesions, where they seemed to be engaged in cytotoxic interactions with HLA-E + oligodendrocytes (5). The concept that LCV-infected B cells are essential APCs in the immunopathogenic process is supported by the potent clinical effects of depleting anti-CD20 mAbs in MS, which were replicated in the marmoset EAE model (46).…”

“…A similar subset of HLA-Erestricted CTLs was identified recently in MS lesions (5), albeit with specificity for myelin basic protein.…”

Quantitative Proteomics of Gut-Derived Th1 and Th1/Th17 Clones Reveal the Presence of CD28+ NKG2D- Th1 Cytotoxic CD4+ T cells

“…However, demonstration of cytotoxic CD4ϩ T cells has been reported in both humans and mice (34 -36). CD4ϩ cytotoxic T cells are reported in acute and chronic infections (28,29,37) and also in immunemediated diseases where they have been found in higher levels (30,32). There are also studies done on Crohn's disease patients that show increased number of cytotoxic CD4ϩ T cells, both from inflammatory and noninflammatory site compared with controls (30,38,39).…”

Exploring the origins of grey matter damage in multiple sclerosis

“…It is important to note that the ability to kill target cells by perforinor Fas/Fas-ligand-mediated lysis, which is typically attributed only to CD8+ T cells, has also been shown for human CD4+ T cells 91 . Furthermore, an antigen-independent lysis mechanism that involves CD56 (or neural cell adhesion molecule, NCAM), which is expressed on natural killer cells and a subset of CD4+ T cells 92 , has been implicated in the lysis of oligodendrocytes 93 .…”