Polymorphisms in TIM-1, a member of the T cell Ig and mucin (TIM) domain family, are associated with relative susceptibility to the development of T helper 2-dominated immune responses such as in allergic asthma. Recent data have also suggested that ligation of TIM-1 can augment T cell activation. We have found that the TIM-1 protein is expressed on CD4 ؉ T cells in vivo after intranasal immunization. Ectopic expression of TIM-1 during T cell differentiation results in a significant increase in the number of cells producing IL-4 but not IFN-␥. Furthermore, TIM-1 expression provides a costimulatory signal that increases transcription from the IL-4 promoter and from isolated nuclear factor of activated T cells͞activating protein-1 (NFAT͞AP-1) elements. Finally, we provide evidence that TIM-1 can be phosphorylated on tyrosine and that TIM-1 costimulation requires its cytoplasmic tail and the conserved tyrosine within that domain. These results constitute evidence that TIM-1 directly couples to phosphotyrosine-dependent intracellular signaling pathways.costimulation ͉ phosphorylation ͉ asthma ͉ cytokines

Ligation of the transmembrane protein T cell Ig and mucin domain (Tim)-1 can costimulate T cell activation. Agonistic Abs to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or costimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in a lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI3K. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation.

T cell Ig and mucin domain protein 2 (TIM-2) has been shown to regulate T cell activation in vitro and T cell-mediated disease in vivo. However, it is still not clear whether TIM-2 acts mainly to augment T cell function or to inhibit it. We have directly examined the function of TIM-2 in murine and human T cell lines. Our results indicate that expression of TIM-2 significantly impairs the induction of NFAT and AP-1 transcriptional reporters by not only TCR ligation but also by the pharmacological stimuli PMA and ionomycin. This does not appear to be due to a general effect on cell viability, and the block in NFAT activation can be bypassed by expression of activated alleles of Ras or calcineurin, or MEK kinase, in the case of AP-1. Thus, our data are consistent with a model whereby TIM-2 inhibits T cell activation.

Recent studies have demonstrated that proteins of the T cell immunoglobulin and mucin domain (TIM) family are important regulators of immune function. Here we discuss the functional effects of TIM proteins on immune responses, how the effects of TIM proteins may be modulated by interactions with ligands and the limited information available on intracellular signals downstream of TIM proteins.

TSLP is primarily an epithelial cell derived cytokine that has been implicated in promoting Th-2 cytokine mediated inflammation at mucosal sites. The TSLP receptor is expressed on a variety of cell types including B cells, monocytes, dendritic cells and mast cells. We have shown earlier that activated CD4+ T cells can also respond to TSLP, express the TSLP receptor and induce IL-4 expression. In this study we have further probed, the effects of TSLP on differentiation and function of other helper T cell lineages. Our data indicate that naive murine CD4+ T cells upon primary activation through the TCR coupled with either TSLP alone or in conjunction with TGF-beta can promote the differentiation and expansion of inducible regulatory T cells (iTregs) indicated by an increased population of FOXP3+ cells and in a manner that requires the TSLP receptor. When added to a cytokine milieu consisting of TGF-β and IL-6 alone or in combination with IL-21 which are known inducers of Th17 differentiation, TSLP downregulates IL-17 production. These data indicate that TSLP can directly influence differentiation of CD4 T cell lineages depending on the cytokine milieu and suggests an immune-regulatory role in disease. Future work is directed at understanding the mechanisms by which TSLP mediates it's effects on T cells and its application in vivo in promoting tolerance and regulating immune responses in allergic and autoimmune diseases.