T cell Ig and mucin 1 (TIM-1) is expressed on in vivo -activated T cells and provides a costimulatory signal for T cell activation

Abstract

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

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

“…6). These results are in agreement with a recent study in which reporter constructs were used to study promoter engagement after murine TIM-1 overexpression (18). In this study, it was shown that TIM-1 expression induced transcription from the IL-4 and NFAT/AP-1 promoters, signals which would be expected to be induced upon TCR activation.…”

“…The activity of ITK is therefore consistent with the hypothesis that TIM-1 is a driver of Th2 T cell differentiation. In contrast, we and others have noted that in mouse systems TIM-1 enhances T cell proliferation and Th2 effector function (i.e., cytokine production) without necessarily dampening Th1 activity (15,18). Thus, whether phosphorylation of ITK is sufficient to drive Th2 differentiation during TIM-1-induced T cell activation remains uncertain.…”

“…First, TIM-1 has been implicated as both a positive and negative regulator of immune responses in mice, depending on the reagents used to study the pathway. As outlined above, anti-TIM-1 mAbs and TIM-1-Fc fusion proteins have been described as having opposing effects on immune responses in a number of systems (11)(12)(13)(14)18). We have recently shown that anti-murine TIM-1 mAbs can block or exacerbate immune responses in mice depending on the specific epitope targeted (29).…”

“…It has been established that TIM-1 mRNA and protein are expressed in both mouse (1,11,18) and human (14,19) CD4 ϩ T cells following activation. To study the downstream signaling effects of TIM-1 expression in human T cells, multiple immortalized lines from ATCC and elsewhere were tested for TIM-1 expression by FACS analysis, but no TIM-1-positive cell lines were found (data not shown).…”

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

“…TIM‐1 is a member of the TIM family of cell surface phosphatidylserine receptors in humans and in mice12 that directly couples to phosphotyrosine‐dependent intracellular signaling pathways13 and provides a costimulatory signal for T cell activation 13. TIM‐1 has recently been found to be predominantly expressed on regulatory B cells 14.…”