TIM-1 AND TIM-2 AS REGULATORS OF T-CELL ACTIVATION

The TIM proteins belong to a novel family of molecules contained within a single gene locus positioned on mouse chromosome 11B1.1 and human chromosome 5q33.2- a locus that has been repeatedly linked with susceptibility to atopy and autoimmune diseases. Early evidences from genetic, epidemiological and immune functional studies have also implicated these proteins in the regulation of immune responses associated with asthma and autoimmunity. However, at the time of commencing these studies there was a paucity of information regarding the underlying molecular basis of TIM function that directed these different effector responses. Based on existing information on putative signaling motifs contained within the TIM protein sequences and early evidence of TIM-2 tyrosine phosphorylation we proposed that TIM-1 and TIM-2 could transduce intra-cellular biochemical signals in response to ligation of the receptor, by coupling to phosphotyrosine dependent signaling mechanisms in order to regulate T cell activation. Employing a combination of biochemical, pharmacological and genetic approaches, our studies establish TIM-1 and TIM-2 proteins as -signal transducing- cell surface receptors. We show that, TIM-2 functions as a negative regulator of T cell activation by inhibiting NFAT/AP-1 dependent transcription. In contrast, TIM-1 can provide a co-stimulatory signal for T cell activation, and augment cytokine and NFAT/AP-1 dependent transcription.TIM-1- mediated signal transduction requires the cytoplasmic tail and the conserved tyrosine 276 contained within the tail. Furthermore, TIM-1 can amplify classical TCR signaling cascades for NFAT/AP-1 dependent transcription and this occurs in a manner that requires the TCR and contribution of most of the key signaling components elicited by the TCR. TIM-1 can also trigger distinct pathways that involve Lck-dependent tyrosine phosphorylation followed by recruitment and activation of p85-PI3K for up-regulation of surface markers associated with T cell activation. In this context, TIM-1 requires Akt to enhance NFAT/AP-1 dependent transcription. Eventually, elucidation of the biochemical signals underlying the mechanistic function of a family of molecules significantly involved in the regulation of T helper cell responses would present targets for therapeutic modulation of Th1 and Th2- type immunity in health and in immune-mediated disease