PDF(Pubmed)
Abstract：
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.Abbreviations: ATG5: autophagy related 5; CBA: cytometric bead array; CCL2/MCP-1: C-C motif chemokine ligand 2; IgG: immunoglobulin G; IL6: interleukin 6; IL10: interleukin 10; IL12: interleukin 12; MFI: mean fluorescence intensity; JAK2: Janus kinase 2; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; pRBCs: parasitized red blood cells; RUBCN: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; STAT4: signal transducer and activator of transcription 4; Th1: T helper 1 cell; Tfh: follicular helper cell; ULK1: unc-51 like kinase 1.
摘要：
寄生虫特异性CD4+Th1细胞反应是控制疟疾感染的主要免疫效应；然而，潜在的监管机制在很大程度上仍然未知。这项研究表明，骨髓细胞中的ATG5缺乏可以通过选择性增强寄生虫特异性CD4Th1细胞反应来显着抑制啮齿动物血液阶段疟疾寄生虫的生长。这种作用与ATG5介导的规范和非规范自噬无关。机械上,ATG5缺乏症抑制了FAS介导的LY6G-ITGAM/CD11bADGRE1/F4/80-细胞的凋亡，随后增加了寄生虫感染小鼠的CCL2/MCP-1产量。LY6G-ITGAM+ADGRE1-细胞衍生的CCL2通过JAK2-STAT4途径与CD4+Th1细胞上的CCR2选择性相互作用以优化其应答。重组CCL2的施用显著促进寄生虫特异性CD4+Th1应答并抑制疟疾感染。最后，我们的研究强调了ATG5在调节骨髓细胞凋亡并依次影响CCL2产生中先前未被识别的作用，选择性地促进CD4+Th1细胞反应。我们的发现为免疫干预和有效抗疟疾疫苗的开发提供了新的见解。
