Antigen-presenting innate lymphoid cells orchestrate neuroinflammation

Grigg, John B.; Shanmugavadivu, Arthi; Regen, Tommy; Parkhurst, Christopher N.; Ahmed, Aquil; Joseph, Ann Mary; Mazzucco, Michael; Gronke, Konrad; Diefenbach, Andreas; Eberl, Gérard; Vartanian, Timothy; Waisman, Ari; Sonnenberg, Gregory F.

doi:10.1038/s41586-021-04136-4

Cited by 51 publications

(41 citation statements)

References 68 publications

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“…ILC3s are central components of immune homeostasis in mucosal barriers, where they collaborate with the tolerance against commensal bacteria [16,45,46]. ILC3s can intake and process antigens, to later present them in the context of MHC-II to CD4 + T cells [47,48]. This interaction plays a fundamental role in the induction of intestinal commensal bacteria tolerance [49].…”

Section: Discussionmentioning

confidence: 99%

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

Einenkel

Ehrhardt

Zygmunt

et al. 2022

Reprod Biol Endocrinol

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Early pregnancy is marked by placentation and embryogenesis, which take place under physiological low oxygen concentrations. This oxygen condition is crucial for many aspects of placentation, trophoblast function, vascularization and immune function. Recently, a new family of innate lymphoid cells has been found to be expressed at the fetomaternal interface. Among these, type 3 innate lymphoid cells (ILC3) are important antigen presenting cells in the context of MHC-II. The expression of MHC-II on ILC3s during pregnancy is reduced. We tested the hypothesis that low oxygen concentrations reduce the potential of ILC3s to present antigens promoting fetal tolerance.Using an in vitro approach, NCR+ ILC3s generated from cord blood stem cell precursors were incubated under different O2 concentrations in the presence or absence of the pregnancy-related hormones hCG and TGF-β1. The expression of MHC-II, accessory molecules and an activation marker were assessed by flow cytometry. We observed that 1% O2 reduced the expression of the MHC-II molecule HLA-DR as compared to 21% O2 and modulated the relative effects of hCG and TGF-β1.Our data indicate that low oxygen concentrations reduce the antigen presentation potential of NCR+ ILC3s and suggest that it may promote fetal tolerance during the first trimester of pregnancy.

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Section: Discussionmentioning

confidence: 99%

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

Einenkel

Ehrhardt

Zygmunt

et al. 2022

Reprod Biol Endocrinol

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“…A defining feature of TCs was their expression of RORgt -a transcription factor shared by ILC3s. A number of critical roles have been attributed to MHCII + ILC3s, including regulation of cancer immunity, autoimmunity and tolerance to microbiota 8,[26][27][28] . These conclusions are based on experimental MHC class II gene ablation in RORgt-expressing cells as a lineage-specific approach for studying ILC3 function.…”

Section: Discussionmentioning

confidence: 99%

A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

Akagbosu

Tayyebi

Shibu

et al. 2022

Preprint

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Tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development. A second wave of Treg cell differentiation occurs in the periphery, upon exposure to dietary and commensal microbiota derived antigens within the first few weeks of life, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new lineage of tolerogenic RORγt+Aire+ antigen-presenting cells (APC) with a hybrid dendritic cell (DC)-mTEC phenotype, dubbed Thetis cells (TCs), comprising 4 major sub-groups (TC I-IV). We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While TC I bore remarkable homology with Aire+ mTECs, TC IV were specifically enriched for critical molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with onset of intestinal inflammation. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was dispensable for pTreg generation, further implicating TCs as the critical tolerogenic RORγt+ APC. Our studies reveal parallel pathways for establishment of tolerance within the thymus and periphery, marked by involvement of shared cellular and transcriptional programs.

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“…Nevertheless, under some conditions such interactions may also promote immune responses in the intestine as well as in the microenvironment of tumors to facilitate tumor immunity (39). Similarly, in a mouse model of multiple sclerosis, MHC class IIexpressing ILC3s with an inflammatory phenotype were recruited from the circulation to the CNS and promoted myelin-specific T cell responses and neuroinflammation (40). Fetal LTi cells.…”

Section: Innate Lymphocytesmentioning

confidence: 99%

Innate and Innate-like Effector Lymphocytes in Health and Disease

Kaer

Postoak

Song

et al. 2022

The Journal of Immunology

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Lymphocytes can be functionally partitioned into subsets belonging to the innate or adaptive arms of the immune system. Subsets of innate and innate-like lymphocytes may or may not express Ag-specific receptors of the adaptive immune system, yet they are poised to respond with innate-like speed to pathogenic insults but lack the capacity to develop classical immunological memory. These lymphocyte subsets display a number of common properties that permit them to integrate danger and stress signals dispatched by innate sensor cells to facilitate the generation of specialized effector immune responses tailored toward specific pathogens or other insults. In this review, we discuss the functions of distinct subsets of innate and innate-like lymphocytes. A better understanding of the mechanisms by which these cells are activated in different contexts, their interactions with other immune cells, and their role in health and disease may inform the development of new or improved immunotherapies.

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Antigen-presenting innate lymphoid cells orchestrate neuroinflammation

Cited by 51 publications

References 68 publications

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

Innate and Innate-like Effector Lymphocytes in Health and Disease

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Antigen-presenting innate lymphoid cells orchestrate neuroinflammation

Cited by 51 publications

References 68 publications

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

Oxygen regulates ILC3 antigen presentation potential and pregnancy-related hormone actions

A novel RORγt+ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life

Innate and Innate-like Effector Lymphocytes in Health and Disease

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Product

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A novel RORγt⁺ antigen presenting cell type instructs microbiota-dependent regulatory T cell differentiation and tolerance during early life