Regulation of T-cell immunity by T-cell immunoglobulin and mucin domain proteins

Abstract

The ability of T helper (TH) precursor cells to differentiate into T effector populations confers the adaptive immune system with a means to protect the host from microbes and react to "foreign" antigenic tissues. T-cell immunoglobulin and mucin domain (TIM) proteins have recently been shown to be novel and critical regulators of T cell subset-driven dependent immune responsiveness. A dichotomy is emerging as to how Tim-3- and Tim-2- related signals respectively impact TH1 and TH2 responses. By comparison, the influence of the Tim-1 pathway seems to be broader and is probably not restricted to a specific type of T helper response. Beyond the mere control of the TH1/TH2 balance, Tim proteins are likely to target other regulatory components of the T cell response. Likewise, it is tempting to speculate that Tim proteins might also modulate the function of other T helper cell subsets such as TH3, TR1 and TH17 cells, among others.

Figure 1

Tim-3 ensures an effective termination of T_H1 driven immunity and inhibits the function of CD8⁺ T cells. Tim-3 is expressed preferentially by terminally differentiated T_H1 clones, CD4⁺CD25⁺ regulatory T cells and activated CD8⁺ T cells. Interaction between galectin-9 and Tim-3 induces the deletion of antigen-specific T_H1 clones. Galectin-9 is expressed by a variety of cells including regulatory T cells. Tim-3–Tim-3 ligand interaction delivers a negative signal to CD8⁺ T cells that inhibits their proliferation and their cytotoxic functions.

Figure 2

Tim-2 negatively regulates the T_H2 pool size. Tim-2 is preferentially expressed by terminally differentiated T_H2 T cells, whereas Tim-2 ligand is detected on activated antigen presenting cells (such as activated B cells, macrophages, and mature dendritic cells). Sema4A, which has a similar cellular pattern of expression as Tim-2 ligand, interacts with Tim-2 to negatively regulate the T_H2 pool size by inhibiting the proliferation and the secretion of cytokines by T_H2 clones. Sema4A expressed by bone marrow DCs enhances the initiation of the immune response by promoting the proliferation of naïve T cells, whereas Sema4A expressed by T cells enhances their proliferation and the secretion of cytokines by T_H1 clones in an autocrine manner or via T cell–T cell interaction.

Figure 3

Tim-1 regulates the initiation of the T cell immune response. Tim-1 is expressed at low levels on undifferentiated T cells and is upregulated after stimulation. Tim-1 pathway, stimulated at least in part by Tim-4 expressed by splenic APCs, enhances the proliferation of T lymphocytes (CD4 and CD8) and the cytokine production regardless of the nature of differentiated T lymphocytes (T_H1 or T_H2).