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

• Published in: The Journal of immunology (1950) 2013-05, Vol.190 (10), p.4991-4999
• Main Authors: Lee, Sarah Y, Goverman, Joan M
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Central Nervous System - immunology; Dendritic Cells - metabolism; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Hepatitis A Virus Cellular Receptor 2; Inflammation; Interleukin-17 - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Microglia - metabolism; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Myelin Sheath - immunology; Receptors, Virus - genetics; Receptors, Virus - metabolism; Signal Transduction - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300083

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the 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. T cell Ig mucin-3 (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, 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 role in 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 dendritic cells 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.