Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
J Immunol. 2012 Apr 1;188(7):3000-8. doi: 10.4049/jimmunol.1101273. Epub 2012 Mar 2.
Invariant NKT (iNKT) cells are a conserved αβTCR(+) T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). In this study, we investigated the reverse relationship, showing that high neutrophil concentrations suppress the iNKT cell response in mice and humans. Peripheral Vα14 iNKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model iNKT cell Ag α-galactosyl ceramide and expressed lower amounts of the T-box transcription factor 21 and GATA3 transcription factor than did wild-type controls. This influence was extrinsic, as iNKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not iNKT cell genotype. Transcription factor expression was also decreased in primary iNKT cells from the neutrophil-rich bone marrow compared with spleen in wild-type mice. In vitro, the function of both mouse and human iNKT cells was inhibited by coincubation with neutrophils. This required cell-cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased iNKT cell T-box transcription factor 21 and GATA3 expression and α-galactosyl ceramide-induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, iNKT cells from the human peritoneal cavity expressed lower transcription factor levels during neutrophilic peritonitis. Our data reveal a novel regulatory axis whereby neutrophils reduce iNKT cell responses, which may be important in shaping the extent of inflammation.
不变自然杀伤 T(iNKT)细胞是一种保守的αβTCR(+)T 细胞群体，能够迅速产生大量细胞因子，从而激活其他白细胞，包括嗜中性粒细胞（中性粒细胞）。在这项研究中，我们研究了相反的关系，表明高浓度的中性粒细胞会抑制小鼠和人类的 iNKT 细胞反应。自发嗜中性粒细胞小鼠的外周 Vα14 iNKT 细胞对模型 iNKT 细胞 Agα-半乳糖神经酰胺的反应产生的细胞因子减少，并且表达的 T 框转录因子 21 和 GATA3 转录因子的量低于野生型对照。这种影响是外在的，因为混合嵌合小鼠中 iNKT 细胞转录因子的表达取决于中性粒细胞计数，而不是 iNKT 细胞基因型。与野生型小鼠的脾脏相比，来自富含中性粒细胞的骨髓的原代 iNKT 细胞的转录因子表达也减少了。在体外，与中性粒细胞共培养可抑制小鼠和人 iNKT 细胞的功能。这需要与活中性粒细胞的细胞-细胞接触。在小鼠实验性腹膜炎中的中性粒细胞炎症会降低 iNKT 细胞 T 框转录因子 21 和 GATA3 的表达，并抑制体内α-半乳糖神经酰胺诱导的细胞因子产生。用中性粒细胞动员阻断来逆转这一现象。同样，在中性粒细胞性腹膜炎期间，人腹腔中的 iNKT 细胞表达较低的转录因子水平。我们的数据揭示了一种新的调节轴，即中性粒细胞降低 iNKT 细胞反应，这可能在塑造炎症程度方面很重要。
