Crystal structures of the TIM molecules has revealed a unique, conserved structure with ligand-binding sites in the IgV domain (810). TIM-3 was initially identified as a molecule expressed on T helper (Th)-1, but not Th2, cells in mice (11). CD4+and CD8+T cells during HIV and other chronic viral infections has been associated with sustained expression of the inhibitory molecule PD-1, which results in inhibition of T cell expansion and cytokine production (24). However, as not all exhausted cells express PD-1, it is likely that other molecules may contribute to the exhaustion associated with HIV infection and other chronic viral infections. On p.2763of this issue, Jones et al. identify a novel molecular mechanism for T cell exhaustion mediated by the expression of TIM-3 (5). == The inTIMidation of T cells == The TIM family of genes, which consists of eight members in mice and three members in humans (6), is located on chromosome 11 in mice and 5q33 in humansgenetic regions that have been associated with autoimmune and allergic diseases. TIM proteins are type 1 membrane proteins with a structurally conserved immunoglobulin variable (IgV) domain and mucin stalk that connects to an intracellular tail. TIM proteins were initially thought to be expressed specifically on the surface of differentiated effector T cells and to directly regulate their activity, but we now know that TIMs are also expressed on and regulate the function of antigen-presenting cells (7). Crystal structures of the TIM molecules has revealed a unique, conserved structure with ligand-binding sites in the IgV domain (810). TIM-3 was initially identified as a molecule expressed on T helper (Th)-1, but not Th2, cells in mice (11). Interaction between TIM-3 and BMS-663068 Tris its ligand galectin-9 inhibits Th1 responses (12) and induces peripheral tolerance (13,14). As in mice, TIM-3 is preferentially expressed on human Th1 cells, but is also expressed constitutively on macrophages and dendritic cells (DCs) (7). Reduction of TIM-3 expression in T cells using small interfering RNA or blocking antibodies, for example, increases interferon (IFN)- secretion by CD4+T cells (15), further supporting an inhibitory role of TIM-3 in human T cells. Patient studies are consistent with this inhibitory function, as TIM-3 expression is defective on CD4+T cells from patients with autoimmune diseases (15,16). Specifically, T cell clones isolated from the cerebrospinal fluid of patients with multiple sclerosis (MS) express lower levels of TIM-3 and secrete higher levels of IFN compared with clones isolated from healthy control subjects (15). CD4+T cells from MS patients also show altered and delayed kinetics BMS-663068 Tris of TIM-3 upon activation, resulting in lower TIM-3 expression on circulating T cells and are therefore refractory to the blocking effects of TIM-3specific antibodies (16). TIM-1, by contrast, is predominantly expressed on Th2 cells and was first identified as the hepatitis A SKP2 virus cellular receptor 1 (17). A unique polymorphism in the mucin domain of TIM-1 regulates hepatitis A virus infection, and also affects immune responses and resistance to asthma, allergy, and atopy (18). == TIM-3 in chronic BMS-663068 Tris virus infection == T cell exhaustion during HIV infection is accompanied by increased HIV replication and follows a characteristic pattern. T cells first lose the ability to enter into cell cycle, to secrete IL-2, and to mediate cytotoxicity (2,3). Over time, the exhausted cells also lose the ability to secrete other cytokines, such as IFN- and TNF (2,3,19). Initial studies suggested that T cell dysfunction is mediated by sustained PD-1 expression on T cells. Upon activation, T cells up-regulates several inhibitory molecules, including PD-1, which help turn off T cell responses and thus inhibit T cell expansion. A functional role for PD-1/PD-L1 signaling in T cell dysfunction was demonstrated by studies of lymphocytic choriomeningitis virus in mice, simian immune deficiency syndrome.