ATG5 in DCs attenuates anti-malarial cellular immune responses through interfering with TLR2-mediated CD209A/DC-SIGN expression.

It is well established that the function of DCs (dendritic cells) is impaired during malaria infection; however, the underlying mechanisms responsible for this impairment remain poorly understood. In this study, we found that ATG5 (autophagy related 5) deficiency in DCs significantly suppressed the growth of malaria blood-stage parasites, and this effect was independent of both canonical and non-canonical macroautophagy/autophagy pathways in these cells. The reduced parasite growth observed in atg5f/f Itgax/Cd11c-Cre+ mice was associated with an enhanced parasite-specific CD4+ T cell response, which provided crucial support for the functional activation of Plasmodium-specific CD8+ T cells. Mechanistically, ATG5 deficiency led to a marked increase in the expression of the phagocytic receptor CD209A/DC-SIGN on conventional DCs (cDCs), thereby enhancing their capacity to activate Plasmodium-specific CD4+ T cell responses. Furthermore, the expression of CD209A was mediated by the TLR2 (toll-like receptor 2) signaling pathway, which was significantly augmented in the absence of ATG5. Thus, we reveal a novel role for ATG5 in modulating anti-malarial cellular immune responses by influencing TLR2-mediated CD209A expression in cDCs. These findings not only enhance our understanding of impaired DC function during malaria infection but also provide valuable insights for the design of more effective malaria vaccines.Abbreviations: ATG5: autophagy related 5; cDCs: conventional dendritic cells; CFSE: carboxyfluorescein succinimidyl ester; DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; IFNG/IFN-γ: interferon gamma; LAP: LC3-associated phagocytosis; MAPK: mitogen-activated protein kinase; NFKB1/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; pRBCs: parasitized red blood cells; PRRs: pattern recognition receptors; TLR2: toll-like receptor 2; TNF/TNF-α: tumor necrosis factor.