Soluble CD 40‐ligand ( sCD 40 L , sCD 154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection

Summary CD 40/ CD 40‐ligand ( CD 40 L ) signalling is a key stimulatory pathway which triggers the tryptophan ( T rp) catabolizing enzyme IDO in dendritic cells and is immunosuppressive in cancer. We reported IDO ‐induced T rp catabolism results in a T helper type 17 ( Th 17)/regulatory T cell ( T reg ) imbalance, and favours microbial translocation in HIV chronic infection. Here we assessed the link between sCD 40 L , T regs and IDO activity in HIV ‐infected patients with different clinical outcomes. Plasmatic sCD 40 L and inflammatory cytokines were assessed in anti‐retroviral therapy ( ART) ‐naive, ART ‐successfully treated ( ST ), elite controllers ( EC ) and healthy subjects ( HS ). Plasma levels of T rp and its metabolite K ynurenine ( K yn) were measured by isotope dilution tandem mass spectrometry and sCD 14 was assessed by enzyme‐linked immunosorbent assay ( ELISA) . IDO ‐ mRNA expression was quantified by reverse transcription–polymerase chain reaction ( RT–PCR) . The in‐vitro functional assay of sCD 40 L on T reg induction and T cell activation were assessed on peripheral blood mononuclear cells ( PBMCs) from HS . sCD 40 L levels in ART ‐naive subjects were significantly higher compared to ST and HS , whereas EC showed only a minor increase. In ART ‐naive alone, sCD 40 L was correlated with T cell activation, IDO ‐ mRNA expression and CD 4 T cell depletion but not with viral load. sCD 40 L was correlated positively with IDO enzymatic activity ( K yn/ T rp ratio), T reg frequency, plasma sCD 14 and inflammatory soluble factors in all HIV ‐infected patients. In‐vitro functional sCD 40 L stimulation induced T reg expansion and favoured T reg differentiation by reducing central memory and increasing terminal effector T reg proportion. sCD 40 L also increased T cell activation measured by co‐expression of CD 38/human leucocyte antigen D‐related ( HLA ‐ DR) . These results indicate that elevated sCD 40 L induces immunosuppression in HIV infection by mediating IDO ‐induced T rp catabolism and T reg expansion.