Invariant and Noninvariant Natural Killer T Cells Exert Opposite Regulatory Functions on the Immune Response during Murine Schistosomiasis

Abstract

CD1d-restricted natural killer T (NKT) cells represent a heterogeneous population of innate memory immune cells expressing both NK and T-cell markers distributed into two major subsets, i.e., invariant NKT (iNKT) cells, which express exclusively an invariant T-cell receptor (TCR) ␣ chain (V␣14J␣18 in mice), and non-iNKT cells, which express more diverse TCRs. NKT cells quickly produce Th1-and/or Th2-type cytokines following stimulation with glycolipid antigen (Ag) and, through this property, play potent immunoregulatory roles in autoimmune diseases, cancer, and infection. No study has addressed the role of NKT cells in metazoan parasite infections so far. We show that during murine schistosomiasis, the apparent frequency of both iNKT cells and non-iNKT cells decreased in the spleen as early as 3 weeks postinfection (p.i.) and that both populations expressed a greater amount of the activation marker CD69 at 6 weeks p.i., suggesting an activated phenotype. Two different NKT-cell-deficient mouse models, namely, TCR J␣18 ؊/؊ (exclusively deficient in iNKT cells) and CD1d؊/؊ (deficient in both iNKT and non-iNKT cells) mice, were used to explore the implication of these subsets in infection. We show that whereas both iNKT and non-iNKT cells do not have a major impact on the immune response during the early phase (1 and 4 weeks) of infection, they exert important, although opposite, effects on the immune response during the acute phase of the disease (7 and 12 weeks), after schistosome egg production. Indeed, iNKT cells contribute to Th1 cell differentiation whereas non-iNKT cells might be mostly implicated in Th2 cell differentiation in response to parasite Ag. Our findings suggest, for the first time, that helminths activate both iNKT and non-iNKT cells in vivo, enabling them to differentially influence the Th1/Th2 balance of the immune response.

Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid

“…Several studies on experimental models of autoimmune diseases, parasitic diseases, and antitumor immunity suggest that type I and type II NKT cells play opposite or cross-regulating roles (24,25,33,34). Thus, sulfatide-reactive type II NKT cells suppress antitumor immunity in several tumor models, whereas type I NKT cells promote immune responses against cancer (24,35).…”

NKT Cells in Tumor Immunity: Opposing Subsets Define a New Immunoregulatory Axis

“…This finding was interpreted to mean that type II NKT cells were proinflammatory in this disease whereas type I NKT cells might counteract the effect of type II when both were present. Opposite effects of these two types of NKT cells were also suggested in acute murine schistosomiasis after egg deposition, at which time CD1d KO mice lacking both subtypes had reduced Th2 cytokine production whereas J␣18KO mice lacking only type I NKT cells had reduced IFN-␥ responses (117).…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…In some pathologic conditions, vNKT cells and iNKT cells exert opposing functions in immune regulation. 72,[75][76][77][78][79] To verify this, J␣18 Ϫ/Ϫ mice were reconstituted using pure iNKT cells. In this condition, although the kinetics of animal death was different than that of WT animals, 80% of mice died of infection.…”

“…80 Attempts are under way to investigate these issues and to identify other functions of iNKT cells in DENV-associated disease. In parallel, because iNKT cells and vNKT cells might have opposing roles during infection and inflammation, 72,[75][76][77][78][79] it would be interesting to examine the role of both subsets and their interplay during DENV infection.…”