TLR–CD40 Cross-Talk in Anti-Leishmanial Immune Response

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and activate innate immune cells to induce cytokines and co-stimulatory molecules such as CD40 and to enhance antigen presentation to T cells (1) that, upon activation, can either eliminate or support the pathogen (2). Herein, we propose that this duality in TLR functions results from their cross-talk with CD40. While all TLRs enhance CD40 expression, CD40 augments the expression of only TLR9 (3). As both CD40 and TLR9 induce expression of IL-12, a cytokine that induces the IFN-γ secreting Th1 cell differentiation (4), the CD40–TLR9 cross-regulation implies a positive feedback loop. By contrast, TLR1–TLR2 heterodimer down-regulates TLR9 expression (5) and antagonizes the development of Th1 response but favors the differentiation of regulatory T (T-reg) cells (Pandey et al., unpublished observation). Low CD40 expression levels in dendritic cells also promote T-reg cell differentiation (6). This duality can emerge from the sharing of signaling molecules. CD40 induces TRAF6-mediated, ERK-1/2-dependent IL-10 (7), which can inhibit the TLR-induced p38-MAPK activation and IL-12 production, antagonizing Th1 development. CD40-induced TRAF3-dependent p38-MAPK activation (7) can synergize with the TLR-activated p38-MAPK-dependent IL-12 production and Th1 differentiation. Using Leishmania infection, we show that the TLR–CD40 cross-talk can induce contrasting anti-leishmanial immune responses. Leishmania, a protozoan parasite, lives in macrophages. Leishmania expresses lipophosphoglycan (LPG), proteoglycans, flagellin, and profilin for possible recognition by the host cell-expressed TLRs. Recognition of the Leishmania-expressed PAMPs results in differential immune responses, which can either reduce or exacerbate Leishmania infection. As TLRs modulate the expression of CD40, a co-stimulatory molecule whose expression levels modulate anti-leishmanial T cell responses, we propose that TLR–CD40 cross-talk significantly regulate the outcome of an anti-leishmanial immune response.