Thymic regulatory T cells arise via two distinct developmental programs

Owen, David L.; Mahmud, Shawn A.; Sjaastad, Louisa E.; Williams, Jason; Spanier, Justin A.; Simeonov, Dimitre R.; Ruscher, Roland; Huang, Weishan; Proekt, Irina; Miller, Corey N.; Hekim, Can; Jeschke, Jonathan C.; Aggarwal, Praful; Broeckel, Ulrich; LaRue, Rebecca S.; Henzler, Christine; Alegre, Maria‐Luisa; Anderson, Mark S.; August, Avery; Marson, Alexander; Zheng, Ye; Williams, Calvin B.; Farrar, Michael A.

doi:10.1038/s41590-018-0289-6

Cited by 183 publications

(227 citation statements)

References 57 publications

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“…Analysis of two discrete thymic Treg cell precursors (CD25 + Foxp3 − and CD25 − Foxp3 lo ) by scRNA‐seq has shown that they have unique transcriptional signatures that were reflective of distinct modes of differentiation 114 . The CD25 + precursors were more enriched in genes associated with stronger TCR signaling while the Foxp3 lo subset had increased expression of adapter genes that could enhance signaling via TNFRs and TCR.…”

Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Chaudhry

Rapaport

et al. 2020

Journal of Leukocyte Biology

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T cells are crucial for the success of immune‐based cancer therapy. Reinvigorating antitumor T cell activity by blocking checkpoint inhibitory receptors has provided clinical benefits for many cancer patients. However, the efficacy of these treatments varies in cancer patients and the mechanisms underlying these diverse responses remain elusive. The density and status of tumor‐infiltrating T cells have been shown to positively correlate with patient response to checkpoint blockades. Therefore, further understanding of the heterogeneity, clonal expansion, migration, and effector functions of tumor‐infiltrating T cells will provide fundamental insights into antitumor immune responses. To this end, recent advances in single‐cell RNA sequencing technology have enabled profound and extensive characterization of intratumoral immune cells and have improved our understanding of their dynamic relationships. Here, we summarize recent progress in single‐cell RNA sequencing technology and current strategies to uncover heterogeneous tumor‐infiltrating T cell subsets. In particular, we discuss how the coupling of deep transcriptome information with T cell receptor (TCR)‐based lineage tracing has furthered our understanding of intratumoral T cell populations. We also discuss the functional implications of various T cell subsets in tumors and highlight the identification of novel T cell markers with therapeutic or prognostic potential.

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Section: Tumor‐infiltrating T Cell Clusters Identified By Scrna‐seqmentioning

confidence: 99%

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Chaudhry

Rapaport

et al. 2020

Journal of Leukocyte Biology

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“…White arrows depict possible further development. Mature thymic Treg populations were generated through two distinct developmental programmes involving CD25 + Treg progenitors and Foxp3 (lo) Treg progenitors . Aire expression promotes the perinatal generation of a distinct compartment of Foxp3 + Tregs that prevents autoimmunity…”

Section: The Comment On Cohn's Tritope Model and The Case For Allele‐mentioning

confidence: 99%

“…The other tTreg population is Aire ‐independent, and its generation might include bone marrow–derived thymic APCs such as plasmacytoid dendritic cells (DCs), conventional DCs and B cells . Recently, using transcriptomics, Owen et al showed two distinct progenitor tTreg populations: CD25 + Treg progenitor (TregP) that employs negative‐selection developmental programme, and Foxp3 lo TregP that co‐opted positive‐selection programme (Figure legend). It is tempting to speculate that at least one of these progenitors stems from the selection on cTECs as proposed 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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“…IL-4 shares a number of its actions with IL-13 (Gieseck et al, 2018), a cytokine that also uses the type 2 IL-4 receptor (see below). Recently, IL-4 was suggested to contribute to Treg development (Owen et al, 2019) and to have a role in homeostasis and repair mechanisms (Harrison et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

2019

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The common cytokine receptor g chain, g c , is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding g c results in X-linked severe combined immunodeficiency in humans, and g c family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.

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Thymic regulatory T cells arise via two distinct developmental programs

Cited by 183 publications

References 57 publications

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

Unravelling the heterogeneity and dynamic relationships of tumor-infiltrating T cells by single-cell RNA sequencing analysis

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

The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

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