Regulation of T cell dependent immune responses by TIM family members

Abstract

The T cell immunoglobulin mucin (TIM) proteins are type I membrane glycoproteins expressed on T cells and containing common structural motifs. While our understanding on the distribution and functions of TIM family members is still incomplete, data from several recent reports indicate that these proteins, together with T cell receptor and costimulatory signals, regulate the expansion and effector functions of T helper cells. In the current review, we provide evidences indicating that TIM-3 is capable of modulating the function of CD4(+)CD25(+) regulatory T cells and inhibiting aggressive Th1 mediated auto- and allo-immune responses. Similarly, additional data suggest that TIM-2 molecules function by negatively regulating Th2 immune responses. In contrast, TIM-1 appears to be an activation molecule for all T cells, although the mechanisms through which TIM-1 activates T cells remain to be elicited.

Figures

Figure 1

Potential mechanisms by which TIM-2 and TIM-3 modulate Th1–Th2 response. (a) TIM-3 and TIM-2 are reciprocally expressed by Th1 and Th2 cells, but TIM-3 is only expressed at the terminal stage of Th1 differentiation. Interaction between TIM-2 and its ligand delivers a negative signal to T cells and downregulates Th2 response (1). At the early stage of differentiation, Th1 cells don't express TIM-3 and expand (2). Terminally differentiated Th1 cells upregulate TIM-3. Interaction of TIM-3 with its ligand on antigen presenting cells and/or CD4+CD25+ regulatory T cells provides a negative signal that limits Th1 cells expansion (3). (b) Blocking the inhibitory interaction between TIM-2 and TIM-2L (either by using a TIM-2 fusion protein or an anti-sema4A mAb) allows the expansion of Th2 cells (1). IL-4, secreted by Th2 cells, reinforces the Th2 deviation by directly inhibiting the Th1 subset (2). Additionally, the blockade of the TIM-2/TIM-2L pathway might enhance CD4+CD25+ regulatory T cells expansion/function by providing a favourable Th2 cytokine milieu and/or by relieving TIM-2+ regulatory T cells from an inhibitory signal (3).

Figure 2

TIM-1-dependent costimulation of T cells. TIM-1 is upregulated on T cell early after activation and interacts with its ligand expressed on the stimulating antigen-presenting cell (APC). TIM-1/TIM-1L interaction provides a positive signal that costimulates T cell activation. Alternatively, TIM-1 expressed on APC might directly deliver a positive signal to the APC, which in turn amplifies T cell activation.