TLR3 is Critical for Polarizing the Tolerogenic Profile of Splenic CD8α ⁻ CD11b ⁺ Dendritic Cells during Leishmania donovani Infection

Dendritic cells (DCs) encounter Leishmania differentially, and the conflict can restrict or disseminate the parasite infection, either by activating or dampening the protective T cell responses and inducing the regulatory T cells. The outcome of this conflict depends on the species of Leishmania , infection tenure, DC subtypes, and, importantly, the DC‐stimulating chemical and physical mediators. The critical balance between splenic cDC1 (CD8α + CD11b − ) and cDC2 (CD8α − CD11b + ) determines the infection severity. However, the influence of TLR(s) on the functional dynamics of cDC1 and cDC2 is still an unexplored area. Our study explored that the expression, activation, and deactivation of TLR3 could influence the cDC2 function during the chronic phase of Leishmania donovani infection. Stimulation of TLR3 induced the expression of anti‐inflammatory mediators like TGF‐β, IL‐10, IDO‐1, and IL‐27 and reduced the pro‐inflammatory cytokines, such as IL‐12 and IL‐6, in cDC2. Homogeneous TLR3‐stimulated cDC2 population from chronically infected hosts not only enhanced the proliferation of IL‐10 producing CD4 + and CD8 + T cells and CD4 + CD25 + FoxP3 + TGF‐β + IL‐10 + regulatory T cells but also promoted the Leishmania donovani amastigote replication in early infected hosts when adoptively transferred to the latter. To the best of our knowledge, this is the first report that suggests that TLR3 is critical for polarizing the tolerogenic profile of the splenic cDC2 and establishes the novelty of TLR3 + CD8α − CD11b + tolerogenic dendritic cells during Leishmania donovani infection.