TIM-1 and TIM-3 Proteins in Immune Regulation

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TIM-1 and TIM-3 Proteins in Immune Regulation (1)

TIM-1

The administration of anti-Tim-1 Ab in vivo was shown to increase levels of IL-4 and IFN-γ but in vitro could only enhance IL-4. These effects are strong enough to abrogate induction of respiratory tolerance. Selective induction of IL-4 production may be due to the association of Tim-1 expression with increased levels of the Th2 transcription factor Gata-3, as seen in a mouse model of asthma. The effects of agonistic (3B3) and antagonistic (RMT1-10) monoclonal antibodies to Tim-1 suggest both possible positive and negative co-stimulatory roles. Tim-1 can be detected on the surface of peritoneal mast cells and bone marrow-derived cultured mast cells. Expression is down-regulated after IgE and antigen stimulation. The addition of Tim-1 to a macrophage cell line resulted in increased cytokine production of TNF-α, IL-6 and IL-10, as well as increased levels of the co-stimulatory molecules B7-1, B7-H1, and PD-L2. At least in the case of PD-L2, the level of expression after Tim-1 treatment was significantly higher than with LPS stimulation. The identification of both Tim-1 and Tim-4 as phosphatidylserine (PS) receptors. Endogenous Tim-4 on macrophages and Tim-1 on kidney cells, as well as transfected Tim-1 or Tim-4 of NIH 3T3 fibroblasts, are all capable of phagocytosing apoptotic cells.

TIM-3

TIM-3 was originally identified through a screen for TH1-specific markers, but since then it has also been found on cytotoxic CD8+ T cells, TH17, Treg, monocytes, dendritic cells, mast cells and microglia. Only galectin-9 has been identified as a ligand for Tim-3. The role of Tim-3 in vivo has been most rigorously tested in EAE, a mouse model of MS. Co-administration of Tim-3 antibody did not alter the onset of EAE but accelerated disease progression. Mice that received myelin PLP (139–151) in incomplete Freund’s adjuvant with Tim-3 antibody developed more severe EAE than their counterparts that were treated with isotype antibody instead. Human monocytes were shown to secrete TNF-α in response to galectin-9 treatment. The pathogenesis associated with EAE is mediated not by TH1 but rather by TH17 cells. Removal of IFN-γ or IFN-γ-secreting cells can actually accelerate disease progression. In a model of PLP (139–151)-induced tolerance, it was observed that splenocytes from mice treated with Tim-3-Ig proliferated and secreted high levels of IL-2 and IFN-γ independently of antigenic stimulation. In studies using galectin-9 to modulate Tim-3 activity, mice receiving galectin-9 were able to delay the rejection of fully allogeneic skin grafts for up to 6 days. A reduction in serum IFN-γ levels of galectin-9 treated mice was observed with a slight increase in both IL-2 and IL-4 levels.

1. E. W. Su, J. Y. Lin, L. P. Kane, TIM-1 and TIM-3 proteins in immune regulation. Cytokine. 44, 9–13 (2008).

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