A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation

Kedmi, Ranit; Najar, Tariq Ahmad; Mesa, Kailin R.; Grayson, Allyssa; Kroehling, Lina; Hao, Yuhan; Hao, Stephanie; Pokrovskii, Maria; Xu, Min; Talbot, Jhimmy; Wang, Jiaxi; Germino, Joe; Lareau, Caleb A.; Satpathy, Ansuman T.; Anderson, Mark S.; Laufer, Terri M.; Aifantis, Iannis; Bartleson, Juliet M.; Allen, Paul M.; Païdassi, Helena; Gardner, James M.; Stoeckius, Marlon; Littman, Dan R.

doi:10.1038/s41586-022-05089-y

Cited by 133 publications

(99 citation statements)

References 52 publications

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“…3j). Of note, CCR6 and SIGLEC-G, which have been suggested to be markers for RORγt + AIRE + cells 16,36,37 , were expressed by TC I and TC II but not by TC III and TC IV (Fig. 3h,i).…”

Section: Transcriptional Programmes Of Thetis Cell Subsetsmentioning

confidence: 93%

“…3h,i). Thus, whereas AIRE + TC I represent RORγt + AIRE + cells, referred to either as Janus cells or RORγt + extra-thymic AIRE-expressing cells (eTACs) in two concurrent analyses of RORγt + APCs 36,37 , TC II-TC IV extend the spectrum of non-ILC3 RORγt + MHCII + cells beyond AIRE-expressing cells (Fig. 3k).…”

Section: Transcriptional Programmes Of Thetis Cell Subsetsmentioning

confidence: 97%

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Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Akagbosu

Tayyebi

Shibu

et al. 2022

Nature

135

114

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Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

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“…3j). Of note, CCR6 and SIGLEC-G, which have been suggested to be markers for RORγt + AIRE + cells 16,36,37 , were expressed by TC I and TC II but not by TC III and TC IV (Fig. 3h,i).…”

Section: Transcriptional Programmes Of Thetis Cell Subsetsmentioning

confidence: 93%

Section: Transcriptional Programmes Of Thetis Cell Subsetsmentioning

confidence: 97%

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Akagbosu

Tayyebi

Shibu

et al. 2022

Nature

135

114

View full text Add to dashboard Cite

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“…The peripheral lymphoid organ plays an essential regulation action against external environmental factors such as microorganisms, chemical exposure, and medications [ 1 , 2 , 3 , 4 ]. Circulating immune cells and cytokines derived from the original local inflammatory peripheral organs influence other organ functions [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Atopic Dermatitis in the Development of Systemic Inflammatory Diseases

Itamura

Sawada

2022

IJMS

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The skin is recognized as a peripheral lymphoid organ that plays an essential defensive action against external environmental stimuli. However, continuous stimulation of these factors causes chronic inflammation at the local site and occasionally causes tissue damage. Chronic inflammation is recognized as a trigger for systemic organ inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that is influenced by various external environmental factors, such as dry conditions, chemical exposure, and microorganisms. The pathogenesis of AD involves various Th2 and proinflammatory cytokines. Recently updated studies have shown that atopic skin-derived cytokines influence systemic organ function and oncogenesis. In this review, we focus on AD’s influence on the development of systemic inflammatory diseases and malignancies.

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“…To restrain bacteria growth, ILC3 number is limited by pyroprosis which reduces the IL-22 levels, representing a potential host defense mechanism ( 80 ). ILC3s not only regulate gut microbial homeostasis through epithelial cells but also present antigens to induce Rorγt + Treg cell differentiation, and produce IL-2 to support their maintenance in the gastrointestinal tract, thus contributing to the maintenance of specific tolerance against the microbiota ( 81 – 83 ).…”

Section: Exchange With Environment and Maintenance Of Barrier Integri...mentioning

confidence: 99%

Innate lymphoid cells: More than just immune cells

2022

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Since their discovery, innate lymphoid cells (ILCs) have been described as the innate counterpart of the T cells. Indeed, ILCs and T cells share many features including their common progenitors, transcriptional regulation, and effector cytokine secretion. Several studies have shown complementary and redundant roles for ILCs and T cells, leaving open questions regarding why these cells would have been evolutionarily conserved. It has become apparent in the last decade that ILCs, and rare immune cells more generally, that reside in non-lymphoid tissue have non-canonical functions for immune cells that contribute to tissue homeostasis and function. Viewed through this lens, ILCs would not be just the innate counterpart of T cells, but instead act as a link between sensory cells that monitor any changes in the environment that are not necessarily pathogenic and instruct effector cells that act to maintain body homeostasis. As these non-canonical functions of immune cells are operating in absence of pathogenic signals, it opens great avenues of research for immunologists that they now need to identify the physiological cues that regulate these cells and how the process confers a finer level of control and a greater flexibility that enables the organism to adapt to changing environmental conditions. In the review, we highlight how ILCs participate in the physiologic function of the tissue in which they reside and how physiological cues, in particular neural inputs control their homeostatic activity.

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A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation

Cited by 133 publications

References 52 publications

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Involvement of Atopic Dermatitis in the Development of Systemic Inflammatory Diseases

Innate lymphoid cells: More than just immune cells

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