SummaryCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.

Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties - parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) - are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA.

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The sustained differentiation of T cells in the thymus cannot be maintained by resident intrathymic (IT) precursors and requires that progenitors be replenished from the bone marrow (BM). In patients with severe combined immunodeficiency (SCID) treated by hematopoietic stem cell transplantation, late T-cell differentiation defects are thought to be due to an insufficient entry of donor BM progenitors into the thymus. Indeed, we find that the intravenous injection of BM progenitors into nonconditioned -chain-associated protein kinase 70 (ZAP-70)-deficient mice with SCID supports short-but not longterm thymopoiesis. Remarkably, we now show that the IT administration of these progenitors produces a significant level of donor-derived thymopoiesis for more than 6 months after transplantation. In contrast to physiologic thymopoiesis, long-term donor thymopoiesis was not due to the continued recruitment of progenitors from the BM. Rather, IT transplantation resulted in the unique generation of a large population of early c-Kit high donor precursors within the thymus. These ZAP-70-deficient mice that received an IT transplant had a significantly increased prothymocyte niche compared with their untreated counterparts; this phenotype was associated with the generation of a medulla. Thus, IT administration of BM progenitors results in the filling of an expanded precursor niche and may represent a strategy for enhancing T-cell differentiation in patients with SCID. (Blood. 2010;115:1913-1920 IntroductionPatients with severe combined immunodeficiency (SCID) present with opportunistic infections that are fatal in infancy. Allogeneic hematopoietic stem cell (HSC) transplantation has long been the mainstay treatment of patients with SCID. The generation of T cells from intravenously administered donor HSCs occurs in the thymus and, as such, requires that they home to this organ before differentiation. In humans, it is not clear whether intravenously injected HSCs or progenitors with T-lineage potential first home to the bone marrow (BM) and are then exported to the thymus or, alternatively, directly enter the thymus. At least in mice, it is known that the latter scenario exists. Specifically, Spangrude and Weissman 1 showed that intravenously injected BM-derived progenitor cells enter the thymus within 4 hours after their infusion. Nevertheless, it appears that the murine thymus is not continuously receptive to the import of hematopoietic progenitors, alternating between refractory and responsive periods. 2 During refractory periods, donor progenitor cells differentiate into T cells only if they are injected directly into the thymus. 2 The intrathymic (IT) transfer of thymocyte progenitors results in thymopoiesis, but this process does not continue long term. [3][4][5] As a consequence, it is thought that long-term thymocyte differentiation requires ongoing migration of donor progenitors from the BM to the thymus. In the case of patients with SCID who receive a HSC transplant, recent studies suggest that this long-term thymopo...

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Patients with severe combined immunodeficiency (SCID) present with opportunistic infections that are almost universally fatal in infancy. The mainstay treatment for these patients is allogeneic hematopoietic stem cell (HSC) transplantation, but sustained polyclonal T cell reconstitution is too often unsatisfactory. Although transplantation is conventionally performed by i.v. administration of HSC, we hypothesized that an intrathymic strategy would be superior. Indeed, several progenitor cell populations are incapable of homing to the thymus, the major site of T cell differentiation, and it appears that there are extensive time periods during which the thymus is refractory to progenitor cell import. To test this hypothesis, nonconditioned infant ZAP-70-deficient SCID mice were intrathymically injected with WT bone marrow progenitor cells, a procedure accomplished without surgical intervention. Upon intrathymic HSC injection, there was a more rapid T cell differentiation, with mature thymocytes detected by 4 weeks after transplantation. Intrathymic injection of HSC also resulted in significantly higher numbers of peripheral T cells, increased percentages of naïve T cells, and more diverse T cell receptor repertoires. Moreover, T cell reconstitution after intrathymic transplantation was obtained after injection of 10-fold fewer donor HSC. Thus, this intrathymic transplantation approach may improve the outcome of SCID patients by enhancing T cell reconstitution. stem cell transplantation ͉ homing ͉ thymus ͉ T cell receptor repertoire

SummaryRegulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co-receptor and low levels of the costimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo.

The thymus forms as an alymphoid thymic primordium with T cell differentiation requiring the seeding of this anlage. This review will focus on the characteristics of the hematopoietic progenitors which colonize the thymus and their subsequent commitment/ differentiation, both in mice and man. Within the thymus, the interplay between Notch1 and IL-7 signals is crucial for the orchestration of T cell development, but the precise requirements for these factors in murine and human thympoeisis are not synonymous. Recent advances in our understanding of the mechanisms regulating precursor entry and their maintenance in the thymus will also be presented.