The TIM (T cell immunoglobulin mucin) proteins are emerging as critical regulators of T helper (Th) cell responses and as potential susceptibility factors for the development of allergic and autoimmune diseases. On page 437, Chakravarti and colleagues add to the developing TIM story by showing that TIM-2 is preferentially expressed on differentiated Th2 cells and inhibits their expansion and function. These molecules, according to senior author Vijay Kuchroo, are not only critical modulators of the CD4+ Th cell response, but are the first reliable markers of differentiated Th cell subsets.
The TIM genes were originally identified as residents of a chromosomal locus that conferred susceptibility to asthma. Since then, this group has shown that TIM3 is expressed exclusively on polarized Th1 cells and dampens their activation. They now show an analogous function for TIM-2 on Th2 cells. Blocking TIM-2 increased the production of Th2 cytokines and protected mice against Th1-driven experimental autoimmune encephalomyelitis, suggesting that TIM-2 normally inhibits excessive activation of Th2 cells.
Although the signals in T cells that drive the expression of TIM2 and TIM3 are not known, their exclusive expression on polarized Th cells (not simply activated T cells) suggests that TIM2 and TIM3 expression may be driven by Th2- and Th1-specific transcription factors, respectively. The structure of the TIM molecules, which most closely resembles the adhesion molecule MAdCAM, suggests that these proteins may also affect lymphocyte trafficking.