ATG5-regulated CCL2/MCP-1 production in myeloid cells selectively modulates anti-malarial CD4⁺ Th1 responses

Parasite-specific CD4(+) Th1 cell responses are the predominant immune effector for controlling malaria infection; however, the underlying regulatory mechanisms remain largely unknown. This study demonstrated that ATG5 deficiency in myeloid cells can significantly inhibit the growth of rodent blood-stage malarial parasites by selectively enhancing parasite-specific CD4(+) Th1 cell responses. This effect was independent of ATG5-mediated canonical and non-canonical autophagy. Mechanistically, ATG5 deficiency suppressed FAS-mediated apoptosis of LY6G- ITGAM/CD11b(+) ADGRE1/F4/80- cells and subsequently increased CCL2/MCP-1 production in parasite-infected mice. LY6G(- )ITGAM(+) ADGRE1(-) cell-derived CCL2 selectively interacted with CCR2 on CD4(+) Th1 cells for their optimized responses through the JAK2-STAT4 pathway. The administration of recombinant CCL2 significantly promoted parasite-specific CD4(+) Th1 responses and suppressed malaria infection. Conclusively, our study highlights the previously unrecognized role of ATG5 in modulating myeloid cells apoptosis and sequentially affecting CCL2 production, which selectively promotes CD4(+ )Th1 cell responses. Our findings provide new insights into the development of immune interventions and effective anti-malarial vaccines.