Toll‐like receptors and CD 40 modulate each other's expression affecting L eishmania major infection

Summary Toll‐like receptors ( TLR s) recognize pathogen‐associated molecular patterns and results in innate immune system activation that results in elicitation of the adaptive immune response. One crucial modulator of the adaptive immune response is CD 40. However, whether these molecules influence each other's expression and functions is not known. Therefore, we examined the effects of TLRs on CD 40 expression on macrophages, the host cell for the protozoan parasiteLeishmania major . While polyinosinic‐polycytidylic acid [poly (I: C )], a TLR‐ 3 ligand, lipopolysaccharide ( LPS ), a TLR‐ 4 ligand, imiquimod, a TLR‐ 7/8 ligand and cytosine–phosphate–guanosine ( CpG ), a TLR‐ 9 ligand, were shown to enhance CD 40 expression, CD 40 stimulation enhanced only TLR‐ 9 expression. Therefore, we tested the synergism between CD 40 and CpG in anti‐leishmanial immune response. InLeishmania ‐infected macrophages, CpG was found to reduce CD 40‐induced extracellular stress‐regulated kinase ( ERK )1/2 activation; with the exception of interleukin ( IL )‐10, these ligands had differential effects on CD 40‐induced IL ‐1α, IL ‐6 and IL ‐12 production. CpG significantly enhanced the anti‐leishmanial function of CD 40 with differential effects on IL ‐4, IL ‐10 and interferon ( IFN )‐γ production in susceptible BALB /c mice. Thus, we report the first systematic study on CD 40– TLR cross‐talk that regulated the experimentalL. major infection.