IL-15 sustains IL-7R-independent ILC2 and ILC3 development

The signals that maintain tissue-resident innate lymphoid cells (ILC) in different microenvironments are incompletely understood. Here we show that IL-7 receptor (IL-7R) is not strictly required for the development of any ILC subset, as residual cells persist in the small intestinal lamina propria (siLP) of adult and neonatal Il7ra(−/−) mice. Il7ra(−/−) ILC2 primarily express an ST2(−) phenotype, but are not inflammatory ILC2. CCR6(+) ILC3, which express higher Bcl-2 than other ILC3, are the most abundant subset in Il7ra(−/−) siLP. All ILC subsets are functionally competent in vitro, and are sufficient to provide enhanced protection to infection with C. rodentium. IL-15 equally sustains wild-type and Il7ra(−/−) ILC survival in vitro and compensates for IL-7R deficiency, as residual ILCs are depleted in mice lacking both molecules. Collectively, these data demonstrate that siLP ILCs are not completely IL-7R dependent, but can persist partially through IL-15 signalling

IL-1R1 is required for dendritic cell-mediated T cell reactivation within the CNS during West Nile virus encephalitis

Infections of the central nervous system (CNS) with cytopathic viruses require efficient T cell responses to promote viral clearance, limit immunopathology, and enhance survival. We found that IL-1R1 is critical for effector T cell reactivation and limits inflammation within the CNS during murine West Nile virus (WNV) encephalitis. WNV-infected IL-1R1(−/−) mice display intact adaptive immunity in the periphery but succumb to WNV infection caused by loss of virologic control in the CNS with depressed local Th1 cytokine responses, despite parenchymal entry of virus-specific CD8(+) T cells. Ex vivo analysis of CD4(+) T cells from WNV-infected CNS of IL-1R1(−/−) mice revealed impaired effector responses, whereas CD8(+) T cells revealed no cell intrinsic defects in response to WNV antigen. WNV-infected, IL-1R1(−/−) mice also exhibited decreased activation of CNS CD11c(+)CD11b(−)CD103(+) and CD11c(+)CD11b(−)CD8α(+)Dec-205(+) cells with reduced up-regulation of the co-stimulatory molecules CD80, CD86, and CD68. Adoptive transfer of wild-type CD11c-EYFP(+) cells from WNV-infected CNS into WNV-infected IL-1R1(−/−) mice trafficked into the CNS restored T cell functions and improved survival from otherwise lethal infection. These data indicate that IL-1R1 signaling promotes virologic control during WNV infection specifically within the CNS via modulation of CD11c(+) cell–mediated T cell reactivation at this site

TREM2 sustains microglial expansion during aging and response to demyelination

Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter

TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model

SummaryTriggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer’s disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation

Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation

Group 3 ILCs (ILC3s) are innate sources of IL-22 and IL-17 and include lymphoid tissue-inducer (LTi)-like and NKp46(+) subsets. Both depend on RORγt and aryl hydrocarbon receptor, but NKp46(+)ILC3s also require Notch and T-bet for their development and are transcriptionally distinct. The extent to which these subsets have unique functions, especially in the context of T cell– and B cell–sufficient mice, remains largely unclear. To investigate the specific function of NKp46(+)ILC3s among other ILC3 subsets and T cells, we generated mice selectively lacking NKp46(+)ILC3s or all ILC3s and crossed them to T cell–deficient mice, thus maintaining B cells in all mice. In mice lacking T cells, NKp46(+)ILC3s were sufficient to promote inflammatory monocyte accumulation in the anti-CD40 innate colitis model through marked production of GM-CSF. In T cell–competent mice, lack of NKp46(+)ILCs had no impact on control of intestinal C. rodentium infection, whereas lack of all ILC3s partially impaired bacterial control. Thus, NKp46(+)ILC3s have a unique capacity to promote inflammation through GM-CSF–induced accumulation of inflammatory monocytes, but are superseded by LTi-like ILC3s and T cells in controlling intestinal bacterial infection

Two distinct myeloid subsets at the term human fetal-maternal interface

During pregnancy, immune cells infiltrate the placenta at different stages of fetal development. NK cells and macrophages are the most predominant cell types. These immune cells play pleiotropic roles, as they control spiral artery remodeling to ensure appropriate blood supply and maintain long-term tolerance to a true allograft; yet, they must be able to mount appropriate immune defenses to pathogens that may threaten the fetus. Whether the same cell type accomplishes all these tasks or if there are dedicated subsets remains controversial. Here, we identify and characterize two distinct subsets of myeloid cells that differ in their pro-inflammatory/regulatory capacity. While one subset predominantly produces the immune-modulating cytokine IL-10, the second subset has superior capacity to secrete pro-inflammatory mediators, such as IL-1β and IL-6. The putative regulatory myeloid cells also express high levels of inhibitory receptors and their ligands, including programmed cell death 1 (PD1) ligands. Importantly, a large fraction of CD8 and CD4 cells in normal term human placenta are PD1 positive, suggesting that the PD1/PD1 ligands axis might be critical to maintain tolerance during pregnancy.8CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação200356/2014-3; 2014/01925-

Jak3 deficiency blocks innate lymphoid cell development

Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive (AR) severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of the immunosuppressive JAK inhibitors. We find that the B6.Cg-Nr1d1tm1Ven/LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3 generating a SCID phenotype, with an inability to generate antigen-independent professional cytokine-producing innate lymphoid cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC progenitor (ILCP) and the pre-NK cell progenitor (pre-NKP). We further demonstrate that the pan-JAK inhibitor tofacitinib and specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro. Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis (RA) and is under clinical trial for several other immune-mediated conditions. Our data suggests that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy

Transforming Growth Factor-beta Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands

International audienceThe signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor-beta (TGF-beta) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46(+) cells enhanced TGF-beta-imprinting of SG ILCs. Thus, TGF-beta induces SG ILC differentiation by suppressing Eomes. TGF-beta acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-beta imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development