TIM-3 Does Not Act as a Receptor for Galectin-9

T cell immunoglobulin and mucin protein 3 (tim-3) is a type i cell surface protein that was originally identified as a marker for murine t helper type 1 cells. tim-3 was found to negatively regulate murine t cell responses and galectin-9 was described as a binding partner that mediates t cell inhibitory effects of tim-3. moreover,it was reported that like pd-1 the classical exhaustion marker,tim-3 is up-regulated in exhausted murine and human t cells and tim-3 blockade was described to restore the function of these t cells. here we show that the activation of human t cells is not affected by the presence of galectin-9 or antibodies to tim-3. furthermore,extensive studies on the interaction of galectin-9 with human and murine tim-3 did not yield evidence for specific binding between these molecules. moreover,profound differences were observed when analysing the expression of tim-3 and pd-1 on t cells of hiv-1-infected individuals: tim-3 was expressed on fewer cells and also at much lower levels. furthermore,whereas pd-1 was preferentially expressed on cd45ra-cd8 t cells,the majority of tim-3-expressing cd8 t cells were cd45ra+. importantly,we found that tim-3 antibodies were ineffective in increasing anti-hiv-1 t cell responses in vitro,whereas pd-l antibodies potently reverted the dysfunctional state of exhausted cd8 t cells. taken together,our results are not in support of an interaction between tim-3 and galectin-9 and yield no evidence for a functional role of tim-3 in human t cell activation. moreover,our data indicate that pd-1,but not tim-3,is a promising target to ameliorate t cell exhaustion. © 2013 leitner et al.