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GREMI Prize 2010, thesis summary:

iNKT cells, the shift from their historical Th2 paradigm to ambivalence:
a journey underlined by IL-33 knowledge

Elvire Bourgeois

This work was performed at :
unité CNRS UMR 8147 à l’Hôpital Necker à Paris puis unité INSERM U935 à l’Hôpital Paul Brousse à Villejuif.

iNKT (for « invariant natural Killer T ») cells are recognized members of the immune community and are a distinctive subtype of CD1d-restricted T cells involved in many different immune situations including anti-tumoral and infectious responses. Their prompt production of both T helper type 1 (Th1) and Th2 cytokines explains their capacity to deeply affect the rest of the immune system despite their small number . iNKT cells share some characteristics with NK cells and in this regard, they occupy a strategic position between adaptive and innate immunity. iNKT cells are characterized by the expression of an invariant V a 14J a 18 antigen receptor, chiefly paired with V b 8.2 in mice. This invariant receptor recognizes both endogenous and exogenous glycolipid antigens in conjunction with non-polymorphic MHC class I-like CD1d molecules.

IL-33 has recently been identified as a member of the IL-1 family binding to the receptor ST2 which leads to its activation. This cytokine is endowed with pro-Th2 functions, leading us to raise the question of its effect on iNKT cells, which are potent IL-4 producers.

We first report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation.

We then investigated whether IL-33 directly interacts with iNKT cells in vitro to induce cytokine production (Bourgeois et al., 2009). Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN- γ rather than IL-4 production upon TCR engagement, a response depending on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN- γ production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses (Figure 1).

We then addressed the physiologic relevance of our findings by studying the possible implication of iNKT cells in a model of innate cell-driven lung inflammation induced by IL- 33 in vivo (Bourgeois et al., 2011)). Indeed, we knew on the one hand, the requirement of iNKT cells to develop allergic asthma, a Th2-mediated pathology and on the other hand, the pro-asthmatic effect of IL-33.

We observed that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (J α 18 -/- ) mice, as was the local production of eotaxin and KC. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the wild-type inflammatory response in J α 18 -/- mice. Finally, by transferring either iNKT cells from wild type or IFN- g -deficient mice, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN- γ production. We also demonstrated that endogenous IL-12 is requisite for activation and recruitment of iNKT cells into the lung, a finding that could explain that the lung inflammation phenotype of IL-12-deficient mice is similar to that of iNKT cell-deficient mice (Figure 2).