The Influence of T Cell Ig Mucin-3 Signaling on Central Nervous System Autoimmune Disease Is Determined by the Effector Function of the Pathogenic T Cells

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) mediated by self-reactive, myelin-specific T cells. Both CD4+ and CD8+ T cells play important roles in the pathogenesis of MS. MS is studied using experimental autoimmune encephalomyelitis (EAE), an animal model mediated by myelin-specific T cells. Tim-3 is a cell-surface receptor expressed on CD4+ IFN-γ-secreting Th1 cells, and triggering Tim-3 signaling ameliorated EAE by inducing death in pathogenic Th1 cells in vivo. This suggested that enhancing Tim-3 signaling might be beneficial in patients with MS. However, Tim-3 is also expressed on activated CD8+ T cells, microglia, and dendritic cells (DCs), and the combined effect of manipulating Tim-3 signaling on these cell types during CNS autoimmunity is unknown. Furthermore, CD4+ IL-17-secreting Th17 cells also play a rolein MS but do not express high levels of Tim-3. We investigated Tim-3 signaling in EAE models that include myelin-specific Th17, Th1 and CD8+ T cells. We found that preventing Tim-3 signaling in CD4+ T cells altered the inflammatory pattern in the CNS due to differential effects on Th1 versus Th17 cells. In contrast, preventing Tim-3 signaling during CD8+ T cell-mediated EAE exacerbated disease. We also analyzed the importance of Tim-3 signaling in EAE in innate immune cells. Tim-3 signaling in DCs and microglia did not affect the manifestation of EAE in these models. These results indicate that the therapeutic efficacy of targeting Tim-3 in EAE is dependent on the nature of the effector T cells contributing to the disease.

Cytokine-Regulated Neutrophil Recruitment Is Required for Brain but Not Spinal Cord Inflammation during Experimental Autoimmune Encephalomyelitis

“…Astrocytes were sorted from GFAP-GFP transgenic mice as CD45 − GFP + cells and endothelial cells were sorted based on CD31 expression. Microglia and the subset of cells containing macrophages, monocyte and dendritic cells were sorted based on expression of CD45 and CD11b as previously described (14). cDNA was generated using a Power SYBR® Green Cells-to-CT™ Kit (life technologies).…”

Regulation of T cell responses by the receptor molecule Tim-3

“…These results are consistent with the idea that injection of anti-Tim-3 antibodies disrupts a pathway that restrains Th1-dependent responses. Of note, Lee et al [47] reported that Tim-3 KO mice subjected EAE challenge did not show the same dramatic effects on disease caused by injecting Tim-3 antibodies, although changes were observed that suggest Tim-3 suppresses EAE and Th1-driven responses.…”

Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3)

“…Tim-3 was demonstrated to be constitutively expressed on microglia in both mice and humans [7,19]. We verified its expression on the cultured primary microglia by flow cytometry and immunocytochemistry analysis that showed 90.6 ± 4.4% and 93.2 ± 2.4% of microglial cells respectively were positive for the Tim-3 antigen (Fig.…”

“…In addition, consistent with other studies showing Tim-3 participates in the clearance of apoptotic cells [30,31], we demonstrated that Tim-3 is involved in the microglial phagocytosis of apoptotic neurons. A recent study reported that ablation of Tim-3 on microglia does not significantly influence the disease onset, or severity of EAE during a 6-day period of observation [19]. One explanation for this could be that Tim-3 on The signaling pathways underlying Tim-3 regulation of cell function and cell fate remain elusive.…”

“…In healthy mice, Tim-3 was expressed constitutively on microglial cells, and expression of Tim-3 was maintained on microglia during experimental autoimmune encephalomyelitis (EAE), an animal model of MS which is an inflammatory demyelinating disease of the CNS [19]. In vivo administration of Tim-3 blocking antibodies enhanced the clinical and pathological severity of EAE [4], while administration of galectin-9, the known ligand of Tim-3, ameliorated the disease [20].…”