After activation, T cells differentiate into distinct effector populations according to the particular cytokine environment that surrounds them. High levels of IFN-γ generate a Th1 population that contributes to protection against bacteria and viruses, whereas an environment of IL-4 leads to development of Th2 cells that are protective against helminths (1
). Allergic asthma is generally held to occur as a consequence of a dysregulated Th2 response to environmental allergens, as it is characterized by increased levels of the Th2 cytokines IL-4, -5, -9, and -13 (2
). Manipulation of Th2 function has been proposed as a novel strategy for treatment of asthma, and enhancing Th1 responses in allergic individuals has been proposed as one method of such a strategy. In mice, transfer of Th1 cells has been shown to down-regulate pathology induced by transfer of Th2 cells alone, and this inhibition has been shown to be IFN-γ dependent (5
T cell Ig and mucin domain–containing molecule-3 (Tim-3) was described as a transmembrane protein preferentially expressed on Th1 cells (6
). In a Th1-mediated model of experimental allergic encephalomyelitis (EAE), in vivo neutralization of Tim-3 resulted in increased disease severity. Two further studies suggested that Tim-3 function was required for peripheral tolerance and acquisition of transplantation tolerance, respectively (7
). In addition, galectin-9 has recently been identified as the ligand for Tim-3, and it has been demonstrated that administration of galectin-9 induced selective death of Th1 cells and inhibited the development of EAE (9
). Collectively, these studies implied that signaling through Tim-3 may negatively regulate Th1 responses, and thus suppression of Tim-3 may inhibit Th2 responses such as allergic disease through enhancement of a Th1 response.
Tim-3 belongs to a novel family of genes that map to a region of chromosome 11 termed T cell and airway phenotype regulator
), which confers reduced Th2 responsiveness and protects against airway hyperreactivity (AHR) (10
). Experiments with mice have shown that the Tapr
locus might regulate Th cell differentiation during primary antigen-specific responses (10
). Currently, the Tim gene family has eight members, Tim-1–8, and genomic analysis has revealed that an equivalent Tim family of genes exists in humans (11
). Polymorphisms in human Tim-1 and -3 have been associated with atopy, suggesting that the Tim family may have functional roles in human allergic diseases (12
). In mouse, Tim-1–3 are reciprocally expressed by Th2 and Th1 cells during T cell differentiation, but their roles in the development of allergy and atopy have not yet been investigated. Therefore, we have used a monoclonal antibody to Tim-3 to determine the effect of Tim-3 blockade on development of allergen-induced airway pathology and AHR in mice.