NKG2D and Its Ligand MULT1 Contribute to Disease Progression in a Mouse Model of Multiple Sclerosis

Abstract

NKG2D is an activating receptor expressed on the surface of immune cells including subsets of T lymphocytes. NKG2D binds multiple ligands (NKG2DL) whose expression are differentially triggered in a cell type and stress specific manner. The NKG2D-NKG2DL interaction has been involved in autoimmune disorders but its role in animal models of multiple sclerosis (MS) remains incompletely resolved. Here we show that NKG2D and its ligand MULT1 contribute to the pathobiology of experimental autoimmune encephalomyelitis (EAE). MULT1 protein levels are increased in the central nervous system (CNS) at EAE disease peak; soluble MULT1 is elevated in the cerebrospinal fluid of both active and passive EAE. We establish that such soluble MULT1 enhances effector functions (e.g., IFNγ production) of activated CD8 T lymphocytes from wild type but not from NKG2D-deficient (Klrk1−/−) mice in vitro. The adoptive transfer of activated T lymphocytes from wild type donors induced a significantly reduced EAE disease in Klrk1−/− compared to wild type (Klrk1+/+) recipients. Characterization of T lymphocytes infiltrating the CNS of recipient mice shows that donor (CD45.1) rather than endogenous (CD45.2) CD4 T cells are the main producers of key cytokines (IFNγ, GM-CSF). In contrast, infiltrating CD8 T lymphocytes include mainly endogenous (CD45.2) cells exhibiting effector properties (NKG2D, granzyme B and IFNγ). Our data support the notion that endogenous CD8 T cells contribute to passive EAE pathobiology in a NKG2D-dependent manner. Collectively, our results point to the deleterious role of NKG2D and its MULT1 in the pathobiology of a MS mouse model.

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…Such expression was more apparent under inflammatory conditions. Legroux et al have now found that endogenous CD8 T cells contribute to EAE pathobiology in a NKG2D‐dependent manner; similar cytotoxic mechanisms may apply in the marmoset model of EAE (Jagessar et al, ; Legroux et al, ).…”

“…We initially showed that human myelin (myelin basic protein [MBP] peptide) reactive CD8 T cells could induce MHC Class I restricted cytotoxicity of human OLs in vitro (Jurewicz, Biddison, & Antel, 1998 cells contribute to EAE pathobiology in a NKG2D-dependent manner; similar cytotoxic mechanisms may apply in the marmoset model of EAE (Jagessar et al, 2015;Legroux et al, 2019). (Roddy, Clark, Hazleman, Compston, & Scolding, 1994;Zajicek, Wing, Skepper, & Compston, 1995).…”

NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells

“…By using mice with T cell–specific deficiency of NKG2D ( Klrk1 flox Cd4 Cre ), we showed that the selective deletion of NKG2D in T cells was sufficient to ameliorate EAE and arthritis, where it also mirrored the effects obtained using α-NKG2D blocking antibody. Although we cannot exclude that in EAE, within a pool of NKG2D + cells, CD8 + T cells also contribute to the pathology ( Legroux et al, 2019 ), OIA is predominantly a CD4 + T cell–mediated disease, in which CD8 + T cells play no role for the establishment of pathology ( Wong et al, 2006 ). In line with these data, the frequency of NKG2D + CD8 + T cells remained unaltered during the course of disease.…”

Kupffer Cells Regulate Natural Killer Cells Via the NK group 2, Member D (NKG2D)/Retinoic Acid Early Inducible-1 (RAE-1) Interaction and Cytokines in a Primary Biliary Cholangitis Mouse Model

“…Many studies suggest that inappropriate expression of NKG2D or its ligand can cause inflammation and promote autoimmune responses, including those in diseases such as rheumatoid arthritis [ 20 ], colitis [ 21 ], Crohn’s disease [ 22 ], type 1 diabetes [ 23 ], and chronic obstructive pulmonary disease [ 24 ]. We wondered whether RAE-1, an NKG2D ligand in mice [ 25 ], would have a similar effect in PBC mice. We used immunohistochemistry to calculate the expression levels of NKG2D, RAE-1, and F4/80 and found that NKG2D expression was positively correlated with the expression of RAE-1 and F4/80 in PBC mice, a finding that we do not believe is coincidental.…”