Skin and Peripheral Lymph Node Invariant NKT Cells Are Mainly Retinoic Acid Receptor-Related Orphan Receptor t+ and Respond Preferentially under Inflammatory Conditions

INSERM Unité 561/Groupe AVENIR, Hôpital Cochin St Vincent de Paul, Université Descartes, Paris, France.
The Journal of Immunology (Impact Factor: 4.92). 09/2009; 183(3):2142-9. DOI: 10.4049/jimmunol.0901059
Source: PubMed


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 (gamma)t (ROR(gamma)t). These cells respond to their ligand alpha-galactosylceramide (alpha-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 ROR(gamma)t(+) NK1.1(-) iNKT cells express concomitantly CCR6, the integrin alpha-chain alpha(E) (CD103), and IL-1R type I (CD121a), indicating that they might play a role in inflamed epithelia. Accordingly, skin epithelia comprise a major ROR(gamma)t(+) CCR6(+)CD103(+)CD121a(+) NK1.1(-) cell population, reflecting iNKT cell composition in PLNs. Importantly, both skin and draining PLN ROR(gamma)t(+) 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 ROR(gamma)t(+) iNKT cells could play a major role in the skin during immune responses to infection and autoimmunity.

Download full-text


Available from: Gerard Eberl, Oct 22, 2014
  • Source
    • "Each pancreas and salivary gland was directly and individually incubated in RPMI 1640 containing collagenase type VIII (Sigma-Aldrich) and Dnase I (Sigma-Aldrich), and cell suspensions were obtained as described previously [5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We explored in this study the status and potential role of IL-17-producing iNKT cells (iNKT17) in type 1 diabetes (T1D) by analyzing these cells in patients with T1D, and in NOD mice, a mouse model for T1D. Our analysis in mice showed an increase of iNKT17 cells in NOD vs control C57BL/6 mice, partly due to a better survival of these cells in the periphery. We also found a higher frequency of these cells in autoimmune-targeted organs with the occurrence of diabetes, suggesting their implication in the disease development. In humans, though absent in fresh PMBCs, iNKT17 cells are detected in vitro with a higher frequency in T1D patients compared to control subjects in the presence of the proinflammatory cytokine IL-1β, known to contribute to diabetes occurrence. These IL-1β-stimulated iNKT cells from T1D patients keep their potential to produce IFN-γ, a cytokine that drives islet β-cell destruction, but not IL-4, with a reverse picture observed in healthy volunteers. On the whole, our results argue in favour of a potential role of IL-17-producing iNKT cells in T1D and suggest that inflammation in T1D patients could induce a Th1/Th17 cytokine secretion profile in iNKT cells promoting disease development.
    PLoS ONE 04/2014; 9(4):e96151. DOI:10.1371/journal.pone.0096151 · 3.23 Impact Factor
  • Source
    • "CD4- population [15] and express the marker for recent thymic emigrant and nature-regulatory T cells neuropilin-1 [16]. Additionally, iNKT-17 cells express molecules that are usually characteristic of Th17 cells such as the orphan nuclear receptor RORγt, the IL-23 receptor (IL-23R), and the chemokine receptor CCR6 [17,22,23]. Although it has become clear that iNKT-17 represents a unique iNKT sublineage with important functions in the pathogenesis of diseases, the signal control for the generation/maintenance of this sublineage of iNKT cells is not well understood. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Invariant natural killer T (iNKT) cells play important roles in bridging innate and adaptive immunity via rapidly producing a variety of cytokines. A small subset of iNKT cells produces IL-17 and is generated in the thymus during iNKT-cell ontogeny. The mechanisms that control the development of these IL-17-producing iNKT-17 cells (iNKT-17) are still not well defined. Diacylglycerol kinase ζ (DGKζ) belongs to a family of enzymes that catalyze the phosphorylation and conversion of diacylglycerol to phosphatidic acid, two important second messengers involved in signaling from numerous receptors. We report here that DGKζ plays an important role in iNKT-17 development. A deficiency of DGKζ in mice causes a significant reduction of iNKT-17 cells, which is correlated with decreased RORγt and IL-23 receptor expression. Interestingly, iNKT-17 defects caused by DGKζ deficiency can be corrected in chimeric mice reconstituted with mixed wild-type and DGKζ-deficient bone marrow cells. Taken together, our data identify DGKζ as an important regulator of iNKT-17 development through iNKT-cell extrinsic mechanisms.
    PLoS ONE 09/2013; 8(9):e75202. DOI:10.1371/journal.pone.0075202 · 3.23 Impact Factor
  • Source
    • "Our studies have identified BATF as a common regulator of lineage decisions in the murine immune system that involve the expression of IL-17. BATF joins RORγt in the transcription factor network that promotes the differentiation of IL-17 expressing cells downstream of pathways triggered by TGFβ and IL-6 in T cells [25] and by a pathway dependent on TGFβ, but not IL-6, in iNKT cells [11,26]. These studies have characterized the DN32.D3 iNKT cell line as a model in which the regulation of Il17a gene and protein expression by this lineage can be investigated further. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background BATF plays important roles in the function of the immune system. Batf null mice are deficient in both CD4+ Th17 cells and T follicular helper cells and possess an intrinsic B cell defect that leads to the complete absence of class switched Ig. In this study, Tg mice overexpressing BATF in T cells were used together with Batf null mice to investigate how altering levels of BATF expression in T cells impacts the development and function of a recently characterized population of iNKT cells expressing IL-17 (iNKT-17). Results BATF has a direct impact on IL-17 expression by iNKT cells. However, in contrast to the Th17 lineage where BATF activates IL-17 expression and leads to the expansion of the lineage, BATF overexpression restricts overall iNKT cell numbers while skewing the compartment in vivo and in vitro toward an iNKT-17 phenotype. Conclusions This work is the first to demonstrate that BATF joins RORγt as the molecular signature for all IL-17 producing cells in vivo and identifies BATF as a component of the nuclear protein network that could be targeted to regulate IL-17-mediated disease. Interestingly, these studies also reveal that while the Il17a gene is a common target for BATF regulation in Th17 and iNKT-17 cells, this regulation is accompanied by opposite effects on the growth and expansion of these two cell lineages.
    BMC Immunology 03/2013; 14(1):16. DOI:10.1186/1471-2172-14-16 · 2.48 Impact Factor
Show more