Innate lymphoid cells (ILCs), including NK cells, contribute to barrier immunity and tissue homeostasis. In addition to the role of uterine NK cells in placentation and fetal growth, other uterine ILCs (uILCs) are likely to play roles in uterine physiology and pathology. In this article, we report on the composition of uILCs in the endometrium during the luteal phase and in the decidua during early pregnancy. Whereas nonkiller uILC1s and uILC2s are barely detectable in mouse and not detected in humans, a sizeable population of uILC3s is found in human endometrium and decidua, which are mostly NCR+ and partially overlap with previously described IL-22–producing uterine NK cells. Development of mouse uILC3 is Nfil3 independent, suggesting unique features of uILCs. Indeed, although the cytokine production profile of mouse uILCs recapitulates that described in other tissues, IL-5, IL-17, and IL-22 are constitutively produced by uILC2s and uILC3s. This study lays the foundation to understand how ILCs function in the specialized uterine mucosa, both in tissue homeostasis and barrier immunity and during pregnancy.

Lymph nodes (LNs) have been long considered as comprising few invariant NKT (iNKT) cells, and these cells have not been studied extensively. In this study, we unravel the existence of stable rather than transitional LN-resident NK1.1− iNKT cell populations. We found the one resident in peripheral LNs (PLNs) to comprise a major IL-17-producing population and to express the retinoic acid receptor-related orphan receptor γt (RORγt). These cells respond to their ligand α-galactosylceramide (α-GalCer) in vivo by expanding dramatically in the presence of LPS, providing insight into how this rare population could have an impact in immune responses to infection. PLN-resident RORγt+ NK1.1− iNKT cells express concomitantly CCR6, the integrin α-chain αE (CD103), and IL-1R type I (CD121a), indicating that they might play a role in inflamed epithelia. Accordingly, skin epithelia comprise a major RORγt+ CCR6+CD103+CD121a+ NK1.1− cell population, reflecting iNKT cell composition in PLNs. Importantly, both skin and draining PLN RORγt+ iNKT cells respond preferentially to inflammatory signals and independently of IL-6, indicating that they could play a nonredundant role during inflammation. Overall, our study indicates that RORγt+ iNKT cells could play a major role in the skin during immune responses to infection and autoimmunity.

Primary viral infections, including primary HIV infection, trigger intense activation of the immune system, with marked expansion of CD38(+)CD8(+) T cells. Whether this expansion involves only viral-specific cells or includes a degree of bystander activation remains a matter of debate. We therefore examined the activation status of EBV-, CMV-, and influenza virus (FLU)-specific CD8(+) T cells during primary HIV infection, in comparison to HIV-specific CD8(+) T cells. The activation markers CD38 and HLA-DR were strongly expressed on HIV-specific CD8(+) T cells. Surprisingly, CD38 expression was also up-regulated on CD8(+) T cells specific for other viruses, albeit to a lesser extent. Activation marker expression returned to normal or near-normal values after 1 year of highly active antiretroviral therapy. HIV viral load correlated with CD38 expression on HIV-specific CD8(+) T cells but also on EBV-, CMV-, and FLU-specific CD8(+) T cells. In primary HIV infection, EBV-specific CD8(+) T cells also showed increased Ki67 expression and decreased Bcl-2 expression, compared with values observed in HIV-seronegative control subjects. These results show that bystander activation occurs during primary HIV infection, even though HIV-specific CD8(+) T cells express the highest level of activation. The role of this bystander activation in lymphocyte homeostasis and HIV pathogenesis remains to be determined.

We have shown previously that peripheral lymph node-resident retinoic acid receptor-related orphan receptor γt+ NK1.1− invariant NKT (iNKT) cells produce IL-17A independently of IL-6. In this study, we show that the concomitant presence of IL-1 and IL-23 is crucial to induce a rapid and sustained IL-17A/F and IL-22 response by these cells that requires TCR–CD1d interaction and partly relies on IL-23–mediated upregulation of IL-23R and IL-1R1 expression. We further show that IL-1 and IL-23 produced by pathogen-associated molecular pattern-stimulated dendritic cells induce this response from NK1.1− iNKT cells in vitro, involving mainly TLR2/4-signaling pathways. Finally, we found that IL-17A production by these cells occurs very early and transiently in vivo in response to heat-killed bacteria. Overall, our study indicates that peripheral lymph node NK1.1− iNKT cells could be a source of innate Th17-related cytokines during bacterial infections and supports the hypothesis that they are able to provide an efficient first line of defense against bacterial invasion.

MHC class I-specific inhibitory receptors are expressed by a subset of memory-phenotype CD8+ T cells. Similar to NK cells, MHC class I-specific inhibitory receptors might subserve on T cells an important negative control that participates to the prevention of autologous damage. We analyzed here human CD8+ T cells that express the Ig-like MHC class I-specific inhibitory receptors: killer cell Ig-like receptor (KIR) and CD85j. The cell surface expression of Ig-like inhibitory MHC class I receptors was found to correlate with an advanced stage of CD8+ T cell maturation as evidenced by the reduced proliferative potential of KIR+ and CD85j+ T cells associated with their high intracytoplasmic perforin content. This concomitant regulation might represent a safety mechanism to control potentially harmful cytolytic CD8+ T cells, by raising their activation threshold. Yet, KIR+ and CD85j+ T cells present distinct features. KIR+CD8+ T cells are poor IFN-γ producers upon TCR engagement. In addition, KIR are barely detectable at the surface of virus-specific T cells during the course of CMV or HIV-1 infection. By contrast, CD85j+CD8+ T cells produce IFN-γ upon TCR triggering, and represent a large fraction of virus-specific T cells. Thus, the cell surface expression of Ig-like inhibitory MHC class I receptors is associated with T cell engagement into various stages of the cytolytic differentiation pathway, and the cell surface expression of CD85j or KIR witnesses to the history of qualitatively and/or quantitatively distinct T cell activation events.

Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-β controls the differentiation program of iNKT cells. We demonstrate that TGF-β signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-β involves the concerted action of different pathways of TGF-β signaling. Whereas the Tif-1γ branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1γ/Smad4-independent branch. Thus, these three different branches of TGF-β signaling function in concert as complementary effectors, allowing TGF-β to fine tune the iNKT cell differentiation program.

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Uterine NK cells are innate lymphoid cells (ILC) that populate the uterus and expand during pregnancy, regulating placental development and fetal growth in humans and mice. We have recently characterized the composition of uterine ILCs (uILCs), some of which require the transcription factor NFIL3, but the extent to which NFIL3-dependent cells support successful reproduction in mice is unknown. By mating Nfil3−/− females with wild-type males, here we show the effects of NFIL3 deficiency in maternal cells on both the changes in uILCs during pregnancy and the downstream consequences on reproduction. Despite the presence of CD49a+Eomes− uILC1s and the considerable expansion of residual CD49a+Eomes+ tissue-resident NK cells and uILC3s in pregnant Nfil3−/− mice, we found incomplete remodeling of uterine arteries and decidua, placental defects, and fetal growth restriction in litters of normal size. These results show that maternal NFIL3 mediates non-redundant functions in mouse reproduction.