The Influence of Tim-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) 2013-04, Vol.190 (10), p.4991-4999
• Main Authors: Lee, Sarah Y., Goverman, Joan M.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1300083

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.