Khaitan Alka, Kilberg Max, Kravietz Adam, Ilmet Tiina, Tastan Cihan, Mwamzuka Mussa, Marshed Fatma, Liu Mengling, Ahmed Aabid, Borkowsky William, Unutmaz Derya
New York University School of Medicine, Department of Pediatrics, Division of Infectious Diseases and Immunology, New York, NY, United States of America.
New York University, Department of Microbiology, New York, NY, United States of America.
PLoS One. 2016 Aug 25;11(8):e0161786. doi: 10.1371/journal.pone.0161786. eCollection 2016.
Mucosal-associated invariant T cells (MAIT) are innate T cells restricted by major histocompatibility related molecule 1 (MR1) presenting riboflavin metabolite ligands derived from microbes. Specificity to riboflavin metabolites confers MAIT cells a broad array of host-protective activity against gram-negative and -positive bacteria, mycobacteria, and fungal pathogens. MAIT cells are present at low levels in the peripheral blood of neonates and gradually expand to relatively abundant levels during childhood. Despite no anti-viral activity, MAIT cells are depleted early and irreversibly in HIV infected adults. Such loss or impaired expansion of MAIT cells in HIV-positive children may render them more susceptible to common childhood illnesses and opportunistic infections. In this study we evaluated the frequency of MAIT cells in perinatally HIV-infected children, their response to antiretroviral treatment and their associations with HIV clinical status and related innate and adaptive immune cell subsets with potent antibacterial effector functions. We found HIV+ children between ages 3 to 18 years have significantly decreased CD8+ MAIT cell frequencies compared to uninfected healthy children. Remarkably, CD8 MAIT levels gradually increased with antiretroviral therapy, with greater recovery when treatment is initiated at a young age. Moreover, diminished CD8+ MAIT cell frequencies are associated with low CD4:CD8 ratios and elevated sCD14, suggesting a link with HIV disease progression. Last, CD8+ MAIT cell levels tightly correlate with other antibacterial and mucosa-protective immune subsets, namely, neutrophils, innate-like T cells, and Th17 and Th22 cells. Together these findings suggest that low frequencies of MAIT cells in HIV positive children are part of a concerted disruption to the innate and adaptive immune compartments specialized in sensing and responding to pathogenic or commensal bacteria.
黏膜相关恒定T细胞（MAIT）是受主要组织相容性相关分子1（MR1）限制的天然T细胞，MR1呈递源自微生物的核黄素代谢物配体。对核黄素代谢物的特异性赋予MAIT细胞广泛的宿主保护活性，可抵御革兰氏阴性和阳性细菌、分枝杆菌及真菌病原体。MAIT细胞在新生儿外周血中的水平较低，并在儿童期逐渐扩增至相对丰富的水平。尽管MAIT细胞没有抗病毒活性，但在HIV感染的成年人中会早期且不可逆地耗竭。HIV阳性儿童中MAIT细胞的这种减少或扩增受损可能使他们更容易患常见的儿童疾病和机会性感染。在本研究中，我们评估了围产期感染HIV儿童中MAIT细胞的频率、它们对抗逆转录病毒治疗的反应，以及它们与HIV临床状态以及具有强大抗菌效应功能的相关天然和适应性免疫细胞亚群的关联。我们发现，与未感染的健康儿童相比，3至18岁的HIV+儿童的CD8+ MAIT细胞频率显著降低。值得注意的是，CD8 MAIT水平随着抗逆转录病毒治疗而逐渐升高，在幼年开始治疗时恢复得更好。此外，CD8+ MAIT细胞频率降低与低CD4:CD8比值和sCD14升高相关，这表明与HIV疾病进展有关。最后，CD8+ MAIT细胞水平与其他抗菌和黏膜保护免疫亚群紧密相关，即中性粒细胞、天然样T细胞以及Th17和Th22细胞。这些发现共同表明，HIV阳性儿童中MAIT细胞频率较低是对专门感知和应对致病或共生细菌的天然和适应性免疫区室协同破坏的一部分。
