CD49b defines functionally mature Treg cells that survey skin and vascular tissues

Fan, Xiying; Moltedo, Bruno; Mendoza, Alejandra; Davydov, Alexey N.; Faire, Mehlika B.; Mažutis, Linas; Sharma, Roshan; Pe’er, Dana; Chudakov, Dmitriy M.; Rudensky, Alexander Y.

doi:10.1084/jem.20181442

Cited by 40 publications

(38 citation statements)

References 94 publications

(115 reference statements)

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“…When effector Tregs were further subdivided according to the expression of the CD49b integrin, it was possible to distinguish circulating Tregs: indeed, compared to other districts, the blood and highly vascularized tissues (liver and lung) contained a high frequency of CD49b + effector Tregs that displayed a significantly higher rate of exchange between parabiotic mice (55). It could be hypothesized that CD49b + Tregs may be devoted to continuous tissue patrolling through blood circulation, being able to promptly reach damaged or inflamed tissues (55), while the CD49b − cells may show a certain degree of stable residency and exert on-site repair/regenerative functions in physiological settings. For instance, Tregs localize to the epithelial stem cell niche and promote hair growth at the steady state (56).…”

Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

2020

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Location, location, and location": according to this mantra, the place where living beings settle has a key impact on the success of their activities; in turn, the living beings can, in many ways, modify their environment. This idea has now become more and more true for T cells. The ability of T cells to recirculate throughout blood or lymph, or to stably reside in certain tissues, turned out to determine immunity to pathogens, and tumors. If location matters also for human beings, the inspiring environment of Capri Island has contributed to the success of the EFIS-EJI Ruggero Ceppellini Advanced School of Immunology focused on "T cell memory," held in Anacapri from October 12, 2018 to October 15, 2018. In this minireview, we would like to highlight some novel concepts about T cell migration and residency and discuss their implications in relation to recent advances in the field, including the mechanisms regulating compartmentalization and cell cycle entry of T cells during activation, the role of mitochondrial metabolism in T cell movement, and the residency of regulatory T cells.

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Section: Tissue Regulatory T Cells: Resident or Recirculating?mentioning

confidence: 99%

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

2020

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“…This enhancement is consistent with previous reports (49,50), which also demonstrated an absence of immunosuppressive effects with LHRH receptor-antagonist treatment. Increased Treg and VM cell subpopulations also contributed to early peripheral immune reconstitution (51,52).…”

Section: Discussionmentioning

confidence: 99%

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

et al. 2020

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One of the main consequences of thymus aging is the decrease in naïve T cell output. This condition accelerates at the onset of puberty, and presents as a major clinical complication for cancer patients who require cytoablative therapy. Specifically, the extensive use of chemotherapeutics, such as cyclophosphamide, in such treatments damage thymic structure and eliminate the existing naïve T cell repertoire. The resulting immunodeficiency can lead to increased incidence of opportunistic infections, tumor growth relapse and/or autoimmune diseases, particularly in older patients. Thus, strategies aimed at rejuvenating the aged thymus following chemotherapeutic damage are required. Previous studies have revealed that sex hormone deprivation in male mice is capable of regenerating the thymic microenvironment following chemotherapy treatment, however, further investigation is crucial to identify gender-based differences, and the molecular mechanisms involved during thymus regeneration. Through phenotypic analyzes, we identified gender-specific alterations in thymocytes and thymic epithelial cell (TEC) subsets from the onset of puberty. By middle-age, females presented with a higher number of thymocytes in comparison to males, yet a decrease in their Aire + medullary TEC/thymocyte ratio was observed. This reduction could be associated with an increased risk of autoimmune disease in middle-aged women. Given the concurrent increase in female Aire + cTEC/thymocyte ratio, we proposed that there may be an impediment in Aire + mTEC hi differentiation, and Aire + cTEC hi as its upstream precursor. The regenerative effects of LHRH receptor antagonist, degarelix, on TEC subsets was also less pronounced in middle-aged females compared to males, possibly due to slower progression of thymic involution in the former, which presented with greater TEC hi proportions. Furthermore, following cyclophosphamide treatment, degarelix enhanced thymocyte and mature TEC subset recovery, with faster recovery kinetics observed in females. These events were found to involve both reactivation and proliferation of thymic epithelial progenitor cells. Taken together, the findings from this study portray Hun et al. Gender Disparity in the Aging Thymus a relationship between gender disparity and thymus aging, and highlight the potential benefits of LHRH receptor antagonist treatment for thymic regeneration. Further research is required, however, to determine how gender may impact on the mechanisms underpinning these events.

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“…To compensate for potential inefficiencies in negative selection, the medulla also subverts a fraction of CD4 + SP thymocytes into the Foxp3 + regulatory T cell (Treg) lineage [7]. When exported from the thymus, these cells are highly effective at limiting autoreactive responses initiated by T cells that escape thymic tolerance [8]. As with negative selection in mouse thymus, both mTECs and thymic DCs are key regulators of Foxp3 + Treg development [9,10].…”

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confidence: 99%

Rethinking Thymic Tolerance: Lessons from Mice

Inglesfield

Cosway

Jenkinson

et al. 2019

Trends in Immunology

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In the thymus, distinct cortex and medulla areas emphasize the division of labor in selection events shaping the abT cell receptor repertoire. For example, MHC restriction via positive selection is a unique property of epithelial cells in the thymic cortex. Far less clear are the events controlling tolerance induction in the medulla. By acting in concert through multiple roles, including antigen production/presentation and chemokine-mediated control of migration, we propose that medullary epithelium and dendritic cells collectively enable the medulla to balance T cell production with negative selection and Foxp3 + regulatory T cell (Treg) development. We examine here the features of these medullary resident cells and their roles in T cell tolerance, and discuss how imbalance in the thymus can result in loss of T cell tolerance. Thymic Medulla and the Control of T Cell ToleranceThe thymus produces multiple T cell types that play key roles in both innate and adaptive immune responses. The importance of these responses has now been shown in sister lineages of vertebrates, long after the function of the thymus was proven for jawed vertebrates in the 1960s [1,2]. Indeed, a key feature of adaptive immunity lies in its ability to generate a wide diversity of antigen receptors that target non-self. For T cells, this is achieved by T cell receptor (TCR) gene rearrangements that take place during T cell development in the thymus. Because of the random nature of gene rearrangement, the thymus imposes stringent mechanisms that shape the abTCR repertoire. Such processes are crucial because they ensure that abT cells (see Glossary) leaving the thymus are not only biased towards the recognition of self-MHC proteins but also tolerant to self-antigens. To achieve this the thymus creates a division of labor: the cortex imposes MHC restriction via positive selection, while the medulla imposes T cell tolerance via a combination of negative selection and Foxp3 + Treg development.The generation of abT cells in the thymus involves immature thymocytes being subjected to sequential checkpoints as they undergo intrathymic migration. To ensure that the thymus produces abT cells capable of antigen recognition in peripheral tissues, the cortex supports positive selection of immature CD4 + CD8 + double-positive (DP) thymocytes that recognize selfpeptide/MHC complexes produced and expressed by cortical thymic epithelial cells (cTECs). This process rescues DP thymocytes from cell death and triggers further differentiation, including expression of the chemokine receptor CCR7 that guides newly selected thymocytes into the medulla [3,4].Because positive selection results in the survival of thymocytes that recognize self-peptide/ MHC, additional selection mechanisms ensure that T cell development produces functional thymocytes that are tolerant to self-antigens. The thymic medulla provides a specialized microenvironment to support these events, and medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) combine to enforce two key proces...

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CD49b defines functionally mature Treg cells that survey skin and vascular tissues

Cited by 40 publications

References 94 publications

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

Recirculation and Residency of T Cells and Tregs: Lessons Learnt in Anacapri

Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage

Rethinking Thymic Tolerance: Lessons from Mice

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