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Immunity Jul 2022Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature...
Regulatory T (Treg) cells expressing the transcription factor Foxp3 are an essential suppressive T cell lineage of dual origin: Foxp3 induction in thymocytes and mature CD4 T cells gives rise to thymic (tTreg) and peripheral (pTreg) Treg cells, respectively. While tTreg cells suppress autoimmunity, pTreg cells enforce tolerance to food and commensal microbiota. However, the role of Foxp3 in pTreg cells and the mechanisms supporting their differentiation remain poorly understood. Here, we used genetic tracing to identify microbiota-induced pTreg cells and found that many of their distinguishing features were Foxp3 independent. Lineage-committed, microbiota-dependent pTreg-like cells persisted in the colon in the absence of Foxp3. While Foxp3 was critical for the suppression of a Th17 cell program, colitis, and mastocytosis, pTreg cells suppressed colonic effector T cell expansion in a Foxp3-independent manner. Thus, Foxp3 and the tolerogenic signals that precede and promote its expression independently confer distinct facets of pTreg functionality.
Topics: Forkhead Transcription Factors; Immune Tolerance; T-Lymphocytes, Regulatory; Th17 Cells; Thymocytes
PubMed: 35700740
DOI: 10.1016/j.immuni.2022.05.010 -
Frontiers in Immunology 2022T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the... (Review)
Review
T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.
Topics: Cell Differentiation; Signal Transduction; T-Lymphocyte Subsets; Thymocytes
PubMed: 35958585
DOI: 10.3389/fimmu.2022.946119 -
European Journal of Immunology Sep 2016Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology...
Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez et al. [Eur. J. Immunol. 2016. 46: 2103-2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post-selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive-selection, and increased cell death in response to weak TCR ligands. Thus, SHP1-deficiency shows strong similarities to deficiency in the T-cell specific SHP1-associated protein Themis.
Topics: Animals; Cell Differentiation; Lymphocyte Activation; Mice; Mice, Knockout; Mice, Transgenic; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocytes; Thymocytes; Thymus Gland
PubMed: 27600672
DOI: 10.1002/eji.201646582 -
Frontiers in Immunology 2018About two decades ago, cloning of the autoimmune regulator () gene materialized one of the most important actors on the scene of self-tolerance. Thymic transcription of... (Review)
Review
About two decades ago, cloning of the autoimmune regulator () gene materialized one of the most important actors on the scene of self-tolerance. Thymic transcription of genes encoding tissue-specific antigens (ts-ags) is activated by AIRE protein and embodies the essence of thymic self-representation. Pathogenic AIRE variants cause the autoimmune polyglandular syndrome type 1, which is a rare and complex disease that is gaining attention in research on autoimmunity. The animal models of disease, although not identically reproducing the human picture, supply fundamental information on mechanisms and extent of AIRE action: thanks to its multidomain structure, AIRE localizes to chromatin enclosing the target genes, binds to histones, and offers an anchorage to multimolecular complexes involved in initiation and post-initiation events of gene transcription. In addition, AIRE enhances mRNA diversity by favoring alternative mRNA splicing. Once synthesized, ts-ags are presented to, and cause deletion of the self-reactive thymocyte clones. However, AIRE function is not restricted to the activation of gene transcription. AIRE would control presentation and transfer of self-antigens for thymic cellular interplay: such mechanism is aimed at increasing the likelihood of engagement of the thymocytes that carry the corresponding T-cell receptors. Another fundamental role of AIRE in promoting self-tolerance is related to the development of thymocyte anergy, as thymic self-representation shapes at the same time the repertoire of regulatory T cells. Finally, AIRE seems to replicate its action in the secondary lymphoid organs, albeit the cell lineage detaining such property has not been fully characterized. Delineation of AIRE functions adds interesting data to the knowledge of the mechanisms of self-tolerance and introduces exciting perspectives of therapeutic interventions against the related diseases.
Topics: Adoptive Transfer; Animals; Antigen Presentation; Autoimmune Diseases; Autoimmunity; Biomarkers; Cell Differentiation; Epithelial Cells; Gene Expression Regulation; Humans; Immune Tolerance; Immunomodulation; Polyendocrinopathies, Autoimmune; Signal Transduction; Thymocytes; Transcription Factors; Transcription, Genetic; AIRE Protein
PubMed: 29483906
DOI: 10.3389/fimmu.2018.00098 -
European Journal of Immunology Jul 2017T-cell development is a spatially and temporally regulated process, orchestrated by well-defined contributions of transcription factors and cytokines. Here, we identify...
T-cell development is a spatially and temporally regulated process, orchestrated by well-defined contributions of transcription factors and cytokines. Here, we identify the noncoding RNA miR-142 as an additional regulatory layer within murine thymocyte development and proliferation. MiR-142 deficiency impairs the expression of cell cycle-promoting genes in mature mouse thymocytes and early progenitors, accompanied with increased levels of cyclin-dependent kinase inhibitor 1B (Cdkn1b, also known as p27 ). By using CRISPR/Cas9 technology to delete the miR-142-3p recognition element in the 3'UTR of cdkn1b, we confirm that this gene is a novel target of miR-142-3p in vivo. Increased Cdkn1b protein expression alone however was insufficient to cause proliferation defects in thymocytes, indicating the existence of additional critical miR-142 targets. Collectively, we establish a key role for miR-142 in the control of early and mature thymocyte proliferation, demonstrating the multifaceted role of a single miRNA on several target genes.
Topics: 3' Untranslated Regions; Animals; CRISPR-Cas Systems; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; RNA Processing, Post-Transcriptional; Thymocytes
PubMed: 28471480
DOI: 10.1002/eji.201746987 -
Frontiers in Immunology 2022Sex steroid hormones have major effects on the thymus. Age-related increases in androgens and estrogens and pregnancy-induced increases in progestins all cause dramatic... (Review)
Review
Sex steroid hormones have major effects on the thymus. Age-related increases in androgens and estrogens and pregnancy-induced increases in progestins all cause dramatic thymic atrophy. Atrophy can also be induced by treatment with exogenous sex steroids and reversed by ablation of endogenous sex steroids. Although these observations are frequently touted as evidence of steroid lymphotoxicity, they are often driven by steroid signaling in thymic epithelial cells (TEC), which are highly steroid responsive. Here, we outline the effects of sex steroids on the thymus and T cell development. We focus on studies that have examined steroid signaling , aiming to emphasize the actions of endogenous steroids which, TEC, have remarkable programming effects on the TCR repertoire. Due to the dramatic effects of steroids on TEC, especially thymic involution, the direct effects of sex steroid signaling in thymocytes are less well understood. We outline studies that could be important in addressing these possibilities, and highlight suggestive findings of sex steroid generation within the thymus itself.
Topics: Androgens; Atrophy; Epithelium; Estrogens; Gonadal Steroid Hormones; Humans; Progestins; Receptors, Antigen, T-Cell; Thymocytes
PubMed: 36119041
DOI: 10.3389/fimmu.2022.975858 -
International Archives of Allergy and... 2019MicroRNAs (miRNAs) are a class of endogenous noncoding single-stranded RNAs widely distributed in eukaryotes, which can modulate target gene expression at... (Review)
Review
MicroRNAs (miRNAs) are a class of endogenous noncoding single-stranded RNAs widely distributed in eukaryotes, which can modulate target gene expression at posttranscriptional level and participate in cell proliferation, differentiation, and apoptosis. Related studies have shown that mi-RNAs are instrumental to many aspects of immunity, including various levels of T-cell immunity. In addition, multiple miRNAs have been ascribed key roles in T-cell development, differentiation, and function. In this review, we highlight the current literature regarding the functional role of miRNAs at various stages of thymocyte development. A better understanding of the relationship between miRNAs and thymocyte development is helpful for the exploration of the exact roles of miRNAs in the development and function of the immune system, as well as related clinical diseases.
Topics: Animals; Humans; MicroRNAs; Natural Killer T-Cells; Receptors, Antigen, T-Cell; Thymocytes
PubMed: 30861526
DOI: 10.1159/000496093 -
Trends in Immunology Feb 2018As they differentiate, thymocytes encounter spatially restricted cues critical for differentiation and selection of a functional, self-tolerant T cell repertoire.... (Review)
Review
As they differentiate, thymocytes encounter spatially restricted cues critical for differentiation and selection of a functional, self-tolerant T cell repertoire. Sequential migration of developing T cells through distinct thymic microenvironments is enforced by the ordered expression of chemokine receptors. Herein, we provide an updated perspective on T cell differentiation through the lens of recent advances that illuminate the dynamics of chemokine-driven thymocyte migration, localization, and interactions with stromal cells. We consider these findings in the context of earlier groundwork exploring the contribution of chemokines to T cell development, recent advances regarding the specificity of chemokine signaling, and novel techniques for evaluating the T cell repertoire. We suggest future research should amalgamate visualization of localized cellular interactions with downstream molecular signals.
Topics: Animals; Cell Communication; Cell Differentiation; Cell Movement; Chemokines; Clonal Selection, Antigen-Mediated; Humans; Immune Tolerance; Receptors, Antigen, T-Cell; T-Lymphocytes; Thymocytes; Thymus Gland
PubMed: 29162323
DOI: 10.1016/j.it.2017.10.007 -
International Journal of Molecular... Feb 2018From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing... (Review)
Review
From the thymus to the peripheral lymph nodes, integrin-mediated interactions with neighbor cells and the extracellular matrix tune T cell behavior by organizing cytoskeletal remodeling and modulating receptor signaling. LFA-1 (αLβ2 integrin) and VLA-4 (α4β1 integrin) play a key role throughout the T cell lifecycle from thymocyte differentiation to lymphocyte extravasation and finally play a fundamental role in organizing immune synapse, providing an essential costimulatory signal for the T cell receptor. Apart from tuning T cell signaling, integrins also contribute to homing to specific target organs as exemplified by the importance of α4β7 in maintaining the gut immune system. However, apart from those well-characterized examples, the physiological significance of the other integrin dimers expressed by T cells is far less understood. Thus, integrin-mediated cell-to-cell and cell-to-matrix interactions during the T cell lifespan still represent an open field of research.
Topics: Animals; Antigens; Cell Adhesion; Cell Differentiation; Cell Movement; Extracellular Matrix; Humans; Immunological Synapses; Integrins; Lymphocyte Activation; Signal Transduction; T-Lymphocytes; Thymocytes
PubMed: 29415483
DOI: 10.3390/ijms19020485 -
ELife Jul 2021Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4CD8double negative (DN) thymocytes to generate αβ T cells in the thymus....
Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4CD8double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of impaired DN3 to DN4 thymocyte transition and severely impaired mouse αβ T cell development. Mechanistically, deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from -deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate -deficiency-induced ER stress. Dual loss of and markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.
Topics: Animals; Endoplasmic Reticulum Stress; Endoplasmic Reticulum-Associated Degradation; Endoribonucleases; Female; Inflammation; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Protein Serine-Threonine Kinases; Proteostasis; Receptors, Notch; Thymocytes; Ubiquitin-Protein Ligases; X-Box Binding Protein 1
PubMed: 34240701
DOI: 10.7554/eLife.69975