Virginie Lafont

NKT cells belong to a conserved T lymphocyte subgroup that has been implicated in the regulation of various immune responses, including responses to viruses, bacteria, and parasites. They express a semi-invariant TCR that recognizes glycolipids presented by the nonpolymorphic MHC class I-like molecule CD1d, and upon activation, they produce various pro- and anti-inflammatory cytokines. Recent studies have shed light on the nature of glycolipids and the environmental signals that may influence the production of cytokines by NKT cells and thus, modulate the immune response. To better understand the regulation mechanisms of NKT cells, we explored their behavior following activation by IL-2 and investigated the signaling pathways and biological responses triggered. We demonstrated that IL-2 activates not only STAT3 and -5 and the PI-3K and ERK-2 pathways as in all IL-2 responder cells but also STAT4 as in NK cells and the p38 MAPK pathway as in αβ T cells. We also showed that STAT6 is activated by IL-2 in NKT cells. Moreover, IL-2 induces the production of IFN-γ and IL-4. The ability of IL-2 to induce pro- and anti-inflammatory cytokine production, in addition to proliferation, could open new therapeutic approaches for use in combination with molecules that activate NKT cells through TCR activation.

Human lymphocytes expressing the γδ TCR represent a minor T cell subpopulation found in blood. The majority of these cells express Vγ9Vδ2 determinants and respond to nonpeptidic phosphoantigens. Several studies have shown that, in vivo, the percentage of Vγ9Vδ2 T cells dramatically increases during pathological infection, leading to the hypothesis that they play an important role in the defense against pathogens. However, the specific mechanisms involved in this response remain poorly understood. It has been established that Vγ9Vδ2 T cells display potent cytotoxic activity against virus-infected and tumor cells, thereby resembling NK cells. In this study, we show that, upon stimulation by nonpeptidic Ags, Vγ9Vδ2 T cells express FcγRIIIA (CD16), a receptor that is constitutively expressed on NK cells. CD16 appears to be an activation Ag for Vγ9Vδ2 T cells. Indeed, ligation of CD16 on Vγ9Vδ2 T cells leads to TNF-α production. This TNF-α production, which is dependent (like that induced via the TCR-CD3 complex) on the activation of the p38 and extracellular signal-regulated kinase-2 mitogen-activated protein kinases, can be modulated by CD94 NK receptors. Therefore, it appears that Vγ9Vδ2 T cells can be physiologically activated by two sequential steps via two different cell surface Ags: the TCR-CD3 complex and the FcγRIIIA receptor, which are specific cell surface Ags for T lymphocytes and NK cells, respectively. This strongly suggests that, in the general scheme of the immune response, Vγ9Vδ2 T cells represent an important subpopulation of cells that play a key role in the defense against invading pathogens.

The present study has explored T cell antigen receptor‐regulated serine kinases in human T cells. The results identify two phosphatidylinositol 3‐kinase (PI3K)‐controlled serine kinases operating downstream of the T cell receptor (TCR) in primary T cells: (i) protein kinase B whose activation regulates the phosphorylation of glycogen synthase kinase 3 and (ii) ribosomal S6 kinase 1, a kinase with a critical role in the regulation of protein synthesis and cell growth. T cells express two isoforms of S6k1: a 70 kDa cytoplasmic kinase and an 85 kDa isoform that has a classic nuclear localisation. TCR ligation triggers a parallel engagement of both the 70 and 85 kDa isoforms of S6k1 in a response that requires PI3K function.