Bacterial infection alters the kinetics and function of iNKT cell responses

CD1d-restricted Valpha14 invariant NKT cells (iNKT) are innate-like, immunoregulatory lymphocytes that play critical roles in autoimmunity, tumor surveillance, and infectious disease. Although iNKT cells are activated during microbial infection, the impacts of infection on the function of iNKT cells have not been fully characterized. Using a Listeria monocytogenes (LM) infection model, we found that iNKT cells failed to expand after infection, resulting in prolonged loss in the spleen, in contrast to the typical expansion and contraction of conventional T cells. iNKT cells from LM-infected mice responded more rapidly to secondary LM infection; however, they became functionally hyporesponsive to antigenic challenge for at least 1 month. This infection-induced hyporesponsiveness was also induced by Mycobacteria infection and was more profound in LM-infected, thymectomized mice, suggesting that infection-primed iNKT cells might have altered functionality. Interestingly, activation with alpha-galactosylceramide-loaded dendritic cells was able to overcome infection-induced hyporesponsiveness of iNKT cells, suggesting a role for extrinsic factors in this functional deficit. Taken together, these findings suggest that infection affects iNKT cell responses quantitatively and qualitatively. As humans are under constant microbial insult, predictions of iNKT cell function based on naïve animal models may not accurately reflect iNKT cell behavior in a clinical setting.