Cell-surface proteins of the TIM (T cell immunoglobulin and mucin domain) family have emerged recently as important regulators of immune function. However, virtually nothing is known about the signal transduction mechanisms used by these proteins. We have been particularly interested in understanding the function and regulation of TIM-1, which is expressed preferentially by Th2 effector cells. Extracellular polymorphisms in both human and murine TIM-1 are strongly associated with susceptibility or resistance to the development of asthma. We and others have recently found that TIM-1 can enhance T cell activation and differentiation. TIM-1 expression augments the activation of signaling pathways that target the NFAT and AP-1 transcription factors and appears to lead to a preferential skewing of T cells to the Th2 lineage. Furthermore, we have found that TIM-1 co-stimulatory signaling is mediated by a conserved tyrosine contained within its cytoplasmic tail. We hypothesize that expression of TIM-1 enhances T cell activation and polarization of helper T cells to the Th2 lineage, through phosphotyrosine-dependent co-stimulatory signaling that enhances induction of NFAT and AP-1. We will test this hypothesis with three specific aims.
In Aim 1, we will identify the mechanisms underlying TIM-1's effects on helper T cell differentiation.
In Aim 2, we will identify the kinase(s) responsible for phosphorylation of TIM-1 Y276, signaling proteins recruited to that site and the role of Y276 in vivo through the generation of a Y276F knock-in mouse model.
In Aim 3, we will determine the effects of TIM-1 on cytoplasmic signaling pathways that regulate NFAT and AP-1. Relevance: Allergic asthma develops as the result of inappropriate immune responses to environmental antigens. Completion of the experiments outlined in this proposal will lead to a more complete understanding of a novel cell surface molecule, TIM-1, that has been implicated in immune function and susceptibility to asthma. Such knowledge may result in the identification of novel targets for therapy and/or diagnosis of asthma. ? ? ?
