Aire-expressing ILC3-like cells in the lymph node display potent APC features

Yamano, Tomoyoshi; Dobeš, Jan; Vobořil, Matouš; Steinert, Madlen; Brabec, Tomáš; Zie̜tara, Natalia; Dobešová, Martina; Ohnmacht, Caspar; Laan, Martti; Peterson, Pärt; Beneš, Vladimı́r; Sedláček, Radislav; Hanayama, Rikinari; Kolář, Michal; Klein, Ludger; Filipp, Dominik

doi:10.1084/jem.20181430

Cited by 56 publications

(59 citation statements)

References 61 publications

(72 reference statements)

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“…Interestingly, cells within the LEC 2 cluster shared molecular signatures with LECs positioned at the ceiling of SCS, within the cortical sinuses, and lining lymphatic vessels, including selective expression of Emcn, Ackr4, Ackr2, Klf2, Fabp4 and Cav1 (Iftakhar et al, 2016;Takeda et al, 2019;Ulvmar et al, 2014). We also identified a subtype of dendritic-cell-like cells (Aire + APC), which likely represent the Aire-expressing ILC3-like cells that were described recently (Yamano et al, 2019). Similarly, we detected two subtypes of neutrophils, Neutrophils 1 and 2, which potentially reflect distinct maturation statuses similar to what was recently described for bone marrow neutrophils (Evrard et al, 2018) (Figure S5L and S5M): Neutrophils 1 expressed components of neutrophil granules and 470 effector molecules at high levels, including Elane, Prtn3, Ctsg, Ngp, Ltf, Camp, and Mpo, whereas Neutrophils 2 expressed little or no effector molecules, but elevated levels of pro-inflammatory genes, including leukocyte traffic molecules, chemokines, cytokines, and cytokine receptors such as Sell, Ccl4, Cxcr2, Cxcl2, Ccl6, Il1b, and Csf3r.…”

Section: Scrna-seq Of Ln Cells Nominates Interacting Partners Of Ln-isupporting

confidence: 62%

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Huang

Ziegler

Austin

et al. 2019

Preprint

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Immune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses to immune challenge at peripheral sites, but also within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, single-cell 30 transcriptomics (scRNA-seq), and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that there are at least four discrete subsets of sensory neurons that innervate LNs with a predominance of peptidergic nociceptors, and an innervation pattern that is distinct from that in the surrounding skin. To uncover potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate a draft atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. Using selective optogenetic stimulation of LN-innervating sensory axons, we directly experimentally tested our inferred connections. Acute neuronal activation triggered rapid transcriptional changes preferentially within our top-ranked putative interacting partners, principally endothelium and other nodal stroma cells, as well as several innate leukocyte populations. Thus, LNs are monitored by a unique 40 population of sensory neurons that possesses immunomodulatory potential. 840 and Harvard. J.O

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Section: Scrna-seq Of Ln Cells Nominates Interacting Partners Of Ln-isupporting

confidence: 62%

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Huang

Ziegler

Austin

et al. 2019

Preprint

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“…All these cells are important for central tolerance, and it is tempting to speculate that they might have different roles (see Further discussion below). Moreover, in the periphery, there are bone marrow–derived unique antigen‐presenting cells that can express Aire and be able to impart tolerance like “extrathymic Aire ‐expressing cells” (eTACs) with an interesting phenotype (MHCII hi , CD80 lo , CD86 lo , EpCAM hi , CD45 lo ) and “group 3 innate lymphoid cell” (ILC3)‐like population (with high levels of MHCII and co‐stimulatory molecules), but their roles will not be discussed here.…”

Section: The Dynamic Model Of Tcr V‐region Selection In the Thymusmentioning

confidence: 99%

On integrity in immunity during ontogeny or how thymic regulatory T cells work

Dembić

2019

Scand J Immunol

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The Standard model of T cell recognition asserts that T cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus and that peripheral T cell repertoire has mild self-major histocompatibility complex (MHC) reactivity, known as MHC restriction of foreign antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope models suggest contradictory roles for complementarity-determining regions (CDRs) of the TCRs.Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR-MHC-conserved interaction. I suggest that double (CD4 + CD8 + )-positive (DP) developing thymocytes compete with their αβTCRs for binding to self-pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue-restricted antigens. The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal-centre B cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self-pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4 + Foxp3 + tTregs can be generated by mTECs via Aire-dependent and Aire-independent pathways, and additionally on thymic bone marrow-derived APCs including thymic Aire-expressing B cells. Thymic Tregs differ from the induced peripheral Tregs, which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes' competition for the highest binding to self-pMHC is the co-evolution of species-specific αβTCR V regions with MHC alleles.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Future studies involving FRC-specific deletion of Deaf1 will provide further insight as to whether its downregulation in acute GVHD is solely responsible for reduced PTA expression. Furthermore, the recent finding that LN innate lymphoid cells type 3 (ILC3) express AIRE (46) and the permanent depletion of the ILC3-related LTi population in GVHD shown here could suggest a more general deficit in peripheral antigen display than accountable by injury to the FRC network alone. The FRC PTA gene set we defined from steady-state FRCs was distinct from that expressed by other LN stromal populations and enriched for genes expressed in the classical target organs of chronic GVHD.…”

Section: Discussionmentioning

confidence: 76%

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity

Dertschnig¹,

Evans²,

Sousa³

et al. 2020

Journal of Clinical Investigation

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Aire-expressing ILC3-like cells in the lymph node display potent APC features

Abstract: The identity of peripheral Aire-expressing cells remains poorly understood. This study shows that Aire-expressing cells in peripheral lymph nodes exhibit typical ILC3 characteristics. These cells display potent APC features, suggesting a function in the control of T cell responses.

Cited by 56 publications

References 61 publications

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes

On integrity in immunity during ontogeny or how thymic regulatory T cells work

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity

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