Stunned invariant NKT cells are not anergic, but acquire IL-10-dependent regulatory characteristics (P1052)

Abstract

Abstract Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that after activation produce copious amounts of cytokines, impacting a dazzling variety of different immune reactions. However, it has been reported that strong activation of iNKT cells with the synthetic model antigen α-galactosylceramide (αGalCer) induces a hypo-reactivity that was proposed to be related to anergy. In contrast, here we report, that αGalCer pretreated iNKT cells, referred to here as ‘induced stunned’ iNKT (isNKT) cells, retain their cytotoxic activity and their response to TCR-independent, cytokine-mediated stimulation. Additionally, isNKT cells acquire characteristics of regulatory cells, marked by the expression of PD-1, Neuropilin-1, CD152 and the ability to produce IL-10. Through the production of IL-10, isNKT cells were able to modulate the tumor load of mice challenged with B16 melanoma and to ameliorate the outcome of Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, a subset of iNKT cells with a stunned phenotype and function were present even in untreated mice, and were enriched in adipose tissue, indicating that natural stunned iNKT cells are present in vivo under steady state conditions. Preliminary data suggest that such stunned iNKT cells can also be found in human PBMCs. These data demonstrate that stunned iNKT cells are not anergic but rather acquire a novel functional state with regulatory potential and that they likely represent a novel, distinct iNKT cell subset.