Pathogenic NKT cells attenuate urogenital chlamydial clearance and enhance infertility

Abstract

Urogenital chlamydial infections continue to increase with over 127 million people affected annually, causing significant economic and public health pressures. While the role of traditional MHCI and II peptide presentation is well defined in chlamydial infections, the role of lipid antigens in immunity remains unclear. Natural killer (NK) T cells are important effector cells that recognize and respond to lipid antigens during infections. Chlamydial infection of antigen‐presenting cells facilitates presentation of lipid on the MHCI‐like protein, CD1d, which stimulates NKT cells to respond. During urogenital chlamydial infection, wild‐type (WT) female mice had significantly greater chlamydial burden than CD1d−/− (NKT‐deficient) mice, and had significantly greater incidence and severity of immunopathology in both primary and secondary infections. WT mice had similar vaginal lymphocytic infiltrate, but 59% more oviduct occlusion compared to CD1d−/− mice. Transcriptional array analysis of oviducts day 6 post‐infection revealed WT mice had elevated levels of Ifnγ (6‐fold), Tnfα (38‐fold), Il6 (2.5‐fold), Il1β (3‐fold) and Il17a (6‐fold) mRNA compared to CD1d−/− mice. In infected females, oviduct tissues had an elevated infiltration of CD4+‐invariant NKT (iNKT) cells, however, iNKT‐deficient Jα18−/− mice had no significant differences in hydrosalpinx severity or incidence compared to WT controls. Lipid mass spectrometry of surface‐cleaved CD1d in infected macrophages revealed an enhancement of presented lipids and cellular sequestration of sphingomyelin. Taken together, these data suggest an immunopathogenic role for non‐invariant NKT cells in urogenital chlamydial infections, facilitated by lipid presentation via CD1d via infected antigen‐presenting cells.

Insights into innate immune cell evasion by Chlamydia trachomatis

“…In contrast, there is no significant difference in the severity or incidence of tubal effusion in Jα18-/-(iNKT-deficient) mice compared with WT controls. Thus, non-invariant NKT cells have an immunopathogenic role in urogenital tract chlamydial infection ( 95 ). This partly explains a seemingly contradictory earlier study that NK T cells triggered pathological Th2 responses during chlamydial infection ( 96 ).…”

Enhancement of Macrophage Immunity against Chlamydial Infection by Natural Killer T Cells

“…Natural killer T (iNKT) cells represent a subset of innate lymphocytes that possess the characteristics of NK and αβ T cells. iNKT cells play an essential role in the early stages of immune responses and can also produce cytokines that regulate subsequent adaptive immune responses against infectious pathogens [26,27]. Our previous work examined the interactions of iNKT/NK and iNKT/DC after Chlamydia lung infection and found that iNKT is a critical regulator in innate and adaptive immune responses [28][29][30].…”