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.
Highlights
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, axonal loss, activation of glial cells, and infiltration of immune cells, such as macrophages and lymphocytes [1, 2]
CD8 than CD4 T lymphocytes carried NKG2D but as CD4 T cells were more abundant, NKG2D-expressing CD4 and CD8 T lymphocytes were present in similar number per CNS in wild type mice (Figure 1E)
We demonstrate that the activating receptor NKG2D contributes to the pathogenic properties of T lymphocytes that are recruited to the CNS upon peripheral activation of encephalitogenic T lymphocytes
Summary
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, axonal loss, activation of glial cells, and infiltration of immune cells, such as macrophages and lymphocytes [1, 2]. NKG2D is an activating or co-activating receptor expressed on several immune effector cells. Most human CD8 T lymphocytes and activated mouse CD8 T lymphocytes exhibit NKG2D on NKG2D and MULT1 in EAE their surface as well as a small subpopulation of activated CD4 T lymphocytes in both species [3]. NKG2D can recognize multiple ligands (NKG2DL); they include Rae-1 (α, β, γ, δ, and ε), H60 (a, b, c) and MULT1 in mice; whereas ULBP (1, 2, 3, 4, 5, and 6) and MIC (A and B) are the human NKG2DL [4]. The expression of NKG2DL are regulated at multiple levels (transcription, posttranscription, post-translation, etc.) and vary according to cell type, activation and environmental cues [5,6,7]. Weakly expressed under normal physiological conditions, NKG2DL are strongly induced in response to stress such as inflammation or infection [4, 6]
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