Neutrophilic granulocytes modulate invariant natural killer T cell function in mice and humans

Invariant natural killer T ( i NKT) cells are a conserved αβTCR + T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). Here we investigated the reverse relationship, showing that high neutrophil concentrations suppress the i NKT cell response in mice and humans. Peripheral Vα14 i NKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model i NKT cell antigen αGalCer and expressed lower amounts of the T-bet and GATA3 transcription factors than did wild-type controls. This influence was extrinsic, as i NKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not i NKT cell genotype. Transcription factor expression was also decreased in primary i NKT cells from the neutrophil rich bone marrow compared to spleen in wild-type mice. In vitro, the function of both mouse and human i NKT cells was inhibited by co-incubation with neutrophils. This required cell-cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased i NKT cell T-bet and GATA3 expression and αGalCer induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, i NKT cells from the human peritoneal cavity expressed lower transcription factor levels during neutrophilic peritonitis. Our data reveal a novel regulatory axis whereby neutrophils reduce i NKT cell responses, which may be important in shaping the extent of inflammation.