Abstract
An immunological hallmark of visceral leishmaniasis (VL), caused by Leishmania donovani, is profound immunosuppression. However, the molecular basis for this immune dysfunction has remained ill defined. Since dendritic cells (DCs) normally initiate antileishmanial immune responses, we investigated whether DCs are dysregulated during L. donovani infection and assessed its role in immunosuppression. Accordingly, we determined the regulatory effect of L. donovani on DCs. Notably, it is still unclear whether L. donovani activates or suppresses DCs. In addition, the molecular mechanism and the relevant receptor (or receptors) mediating the immunoregulatory effect of L. donovani on DCs are largely undefined. Here, we report that L. donovani inhibited DC activation/maturation by transmitting inhibitory signals through the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby suppressed antileishmanial immune responses. L. donovani in fact triggered TIM-3 phosphorylation in DCs, which in turn recruited and activated a nonreceptor tyrosine kinase, Btk. Btk then inhibited DC activation/maturation by suppressing the NF-κB pathway in an interleukin-10 (IL-10)-dependent manner. Treatment with TIM-3-specific blocking antibody or suppressed expression of TIM-3 or downstream effector Btk made DCs resistant to the inhibitory effects of L. donovani. Adoptive transfer experiments further demonstrated that TIM-3-mediated L. donovani-induced inhibition of DCs plays a crucial role in the suppression of the antileishmanial immune response in vivo. These findings identify TIM-3 as a new regulator of the antileishmanial immune response and demonstrate a unique mechanism for host immunosuppression associated with L. donovani infection. IMPORTANCE Visceral leishmaniasis (VL), a poverty-related disease caused by Leishmania donovani, is ranked by the World Health Organization as the second largest killer parasitic disease in the world. The protective immune response against VL is primarily regulated by dendritic cells (DCs), which upon activation/maturation initiate an antileishmanial immune response. However, it remains obscure whether L. donovani promotes or inhibits DC activation. In addition, the receptor through which L. donovani exerts immunoregulatory effect on DCs is ill defined. Here, we for the first time report that L. donovani inhibits DC activation and maturation via the T cell immunoglobulin and mucin protein-3 (TIM-3) receptor and thereby attenuates the capacity of DCs to trigger antileishmanial immune responses in vivo. In fact, we demonstrate here that suppression of TIM-3 expression in DCs augments antileishmanial immunity. Our study uncovers a unique mechanism by which L. donovani subverts host immune responses and suggests TIM-3 as a potential new target for immunotherapy against VL.