The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells

A distinct population of Th17 cells develops in the thymus with innate immune cell characteristics, different selection requirements, and skewed TCR gene usage compared with peripheral Th17 cells

NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses

NIK expression in thymic dendritic cells is required for the development of effector T cells and their ability to promote EAE

Common genetic polymorphisms within NFκB-Related genes and the risk of developing invasive aspergillosis

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NF kappa B1, NF kappa B2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non IA) recruited through a collaborative effort involving the aspBlOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4(rs12203592T/T) genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4(AATC) and IRF4(GGTC) haplotypes (not including the IRF4(rs12203592T/T) risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4(rs12203592) SNP Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.- This study was supported by grants PI12/02688 from Fond de Investigaciones Sanitarias (Institute de Salud Carlos III, Madrid, Spain), the ERA-NET PathoGenoMics (03159000A; Ministerio de Ciencia e Innovation PIM2010EPA-00756, Madrid, Spain), the Collaborative Research Center / Transregio 124 FungiNet, the Austrian Science Fundation (FWF I-656-B09), the Fundacao para a Ciencia e Tecnologia (FCT), cofundcd by Programa Operacional Regional do Norte (ON.2-O Novo Norte), the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). Agostinho Carvalho and Cristina Cunha were supported by the Fundacao para a e Tecnologia (FCT), Portugal (IF/00735/2014 and SFRH/BPD/96176/2013, respectively). The PCRAGA trial was supported by an unrestricted grant from Pfizer, which had no involvement or control over the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. This study was also supported by Astellas Pharma Inc. and a donation from Consuelo Gonzalez Moreno, an acute myeloid leukemia survivor.info:eu-repo/semantics/publishedVersio

RelB+^{+} Steady-State Migratory Dendritic Cells Control the Peripheral Pool of the Natural Foxp3+^{+} Regulatory T Cells

Thymus-derived natural Foxp3$^{+}$ CD4$^{+}$ regulatory T cells (nTregs) play a key role in maintaining immune tolerance and preventing autoimmune disease. Several studies indicate that dendritic cells (DCs) are critically involved in the maintenance and proliferation of nTregs. However, the mechanisms how DCs manage to keep the peripheral pool at constant levels remain poorly understood. Here, we describe that the NF-κB/Rel family transcription factor RelB controls the frequencies of steady-state migratory DCs (ssmDCs) in peripheral lymph nodes and their numbers control peripheral nTreg homeostasis. DC-specific RelB depletion was investigated in CD11c-Cre × RelB$^{fl/fl}$ mice (RelB$^{DCko}$), which showed normal frequencies of resident DCs in lymph nodes and spleen while the subsets of CD103$^{-}$ Langerin$^{-}$ dermal DCs (dDCs) and Langerhans cells but not CD103$^{+}$ Langerin$^{+}$ dDC of the ssmDCs in skin-draining lymph nodes were increased. Enhanced frequencies and proliferation rates were also observed for nTregs and a small population of CD4$^{+}$ CD44$^{high}$ CD25$^{low}$ memory-like T cells (Tml). Interestingly, only the Tml but not DCs showed an increase in IL-2-producing capacity in lymph nodes of RelB$^{DCko}$ mice. Blocking of IL-2 in vivo reduced the frequency of nTregs but increased the Tml frequencies, followed by a recovery of nTregs. Taken together, by employing RelB$^{DCko}$ mice with increased frequencies of ssmDCs our data indicate a critical role for specific ssmDC subsets for the peripheral nTreg and IL-2$^{+}$ Tml frequencies during homeostasis

mTORC2 regulates multiple aspects of NKT-cell development and function

Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictorfl/fl CD4cre+ mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT-cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function