Reentry of T cells to the adult thymus is restricted to activated T cells.

Agus, David B.; Surh, Charles D.; Sprent, Jonathan

doi:10.1084/jem.173.5.1039

Cited by 248 publications

(184 citation statements)

References 23 publications

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“…Mature B cells, as shown in this study, and APCs, as shown in other studies (7), do not efficiently circulate to the thymus, and therefore may not deliver Ag to newly developing T cells. It has been suggested that resting mature T cells recirculate into the thymus inefficiently when compared with activated T cells (21,22). In our experiments, we were able to detect a relatively high frequency of mature allogeneic T cells in the thymus.…”

Section: Discussionsupporting

confidence: 65%

Induction of Central Tolerance by Mature T Cells

Tian

Bagley

Forman

et al. 2004

The Journal of Immunology

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Induction of immunological tolerance is highly desirable for the treatment and prevention of autoimmunity, allergy, and organ transplant rejection. Adoptive transfer of MHC class I disparate mature T cells at the time of reconstitution of mice with syngeneic bone marrow resulted in specific tolerance to allogeneic skin grafts that were matched to the T cell donor strain. Mature allogeneic T cells survived long-term in reconstituted hosts and were able to re-enter the thymus. Analysis of T cell development using transgenic mice expressing an alloantigen-reactive TCR revealed that expression of allogeneic MHC class I on adoptively transferred mature T cells mediated negative selection of developing alloreactive T cells in the thymus. Thus, mature allogeneic T cells are able to mediate central deletion of alloreactive cells and induce transplantation tolerance without the requirement for any other alloantigen-expressing cell type.

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Section: Discussionsupporting

confidence: 65%

Induction of Central Tolerance by Mature T Cells

Tian

Bagley

Forman

et al. 2004

The Journal of Immunology

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“…In the absence of CD5, an increased percentage of CD4 1 CD25 1 Foxp3 1 are generated at day 8 of culture, compared with WT FTOC (3.5470.3% versus 2.0270.32%; n 5 10, pr0.05), (Fig. 6A and B), demonstrating that nTreg are thymus derived and do not represent recirculating peripheral T cells homing to the thymus [54,55]. This increase in CD25 1 Foxp3 1 cells was also seen in the DP subpopulation (data not shown).…”

Section: Intracellular Tcr-mediated Signaling In Cd5 à/à Thymocytesmentioning

confidence: 95%

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

et al. 2009

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It has been suggested that high affinity/avidity interactions are required for the thymic selection of Treg. Here, we investigated the role of CD5, a negative regulator of TCR signaling, in the selection and function of ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg). Analysis of CD5 À/À mice showed a significant increase in the percentage and absolute numbers of CD4 1 CD25 1 Foxp3 1 thymocytes and peripheral T lymphocytes, compared with BALB/c mice. Thymi from CD5 À/À mice showed reduced cellularity due to increased apoptosis, which preferentially affected naïve T cells. To characterize nTreg selection at the molecular level we investigated the phosphorylation of Erk, c-Cbl, PI3K and Akt. CD5 À/À nTreg showed increased basal levels of p-Erk compared with wild-type nTreg. Interestingly, in response to CD3 plus CD28 costimulation, CD5 À/À naïve T cells but not CD5 À/À nTreg showed lower levels of p-Akt. Finally, CD5 À/À nTreg were thymus-derived and fully functional. We conclude that the enrichment of nTreg observed in the absence of CD5 signaling is due to de novo generation of nTreg and selective reduction of CD4 1 CD25 À naïve thymocytes. Furthermore, we provide new evidence supporting a potential role of CD5 in thymocyte survival, through a mechanism that may involve the phosphorylation of Akt.Key words: CD5 . Development . Treg . Signaling . Thymocyte IntroductionThe maintenance of immunological self-tolerance is a fundamental property of the immune system besides the clearance of pathogenic agents. Central and peripheral mechanisms exist to ensure the elimination or inactivation of potentially harmful autoreactive T cells. Negative selection in the thymus induces the deletion of most self-reactive T-cell clones during T-cell development [1]. However, some autoreactive T cells escape from clonal deletion and need to be controlled by peripheral mechanisms including peripheral T-cell deletion by activation-induced cell death [2], T-cell anergy [3] and T-cell-mediated suppression [4].Recently, non-deletional mechanisms of central tolerance have been re-evaluated, such as the development of thymus-derived Treg [5]. These cells are currently known as ''naturally occurring'' CD4 1 CD25 1 Treg (nTreg), which represent a small population (5-10%) of peripheral CD4 1 T cells and are characterized by high levels of surface CD25 and by the expression of Foxp3, a transcription factor, identified as a key regulator of nTreg development and function [6]. In addition, nTreg also express activation markers such 2233as CTLA-4, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, OX40 and CD103 [7,8]. nTreg were first studied for their role in maintaining self-tolerance [9], preventing autoimmune diseases [10] and the development of harmful immunopathological responses [11]. However, nTreg can also participate in modulating adaptive immunity to viruses, bacteria and parasites affecting favorably or detrimentally the outcome of immune responses to infections [12,13].The mechanisms of suppression used by Treg...

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“…Interestingly, the vast majority of the small numbers of cells in the thymus (Ͻ 10 6 ) at this stage were also CD45.1 ϩ (Figure 3B), reflecting the previously described recirculation of activated mature donor T cells. 22 Finally, the FoxP3 ϩ T reg cells in the periphery of BM transplant recipients were also all CD45.1 ϩ and thus also derived from the mature donor T-cell inoculum within the graft ( Figure 3C). Having demonstrated that all T cells in the BM transplant recipients were peripherally expanded from the mature donor T-cell inoculum at this time, we next quantified donor FoxP3 Ϫ CD4 ϩ effector (T effector ) and T reg expansion in the periphery of WT and RelB Ϫ/Ϫ BMC recipients.…”

Section: Abrogation Of Gvhd Is Associated With Normal Donor T Reg Expmentioning

confidence: 99%

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

MacDonald

Kuns

Rowe

et al. 2007

Blood

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IntroductionAllogeneic bone marrow transplantation (BMT) is the definitive curative therapy for the majority of hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal tract, and liver are preferentially damaged by the transplanted donor immune system. The therapeutic potential of BMT relates to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer cells. 1 GVHD occurs in the majority (50%-70%) of recipients and is largely responsible for the high rate of mortality associated with allogeneic BMT. There is thus a pressing need for new treatment approaches to both prevent and treat GVHD, ideally without inhibiting GVL.The complex interactions resulting in the generation of T-cellmediated alloimmune responses depend on antigen presentation, cognate interactions between donor T cells and antigen-presenting cells (APCs), and the concomitant production of soluble and membrane-bound costimulatory molecules by APCs and T cells (reviewed in Morris et al 2 ). The initiation of GVHD absolutely depends on the presence of mature donor T cells in the graft. 2 Thus, although TLR signaling undoubtedly contributes to the activation of APCs early after transplantation, 3 it is likely that donor T cells provide the most critical signal. In this regard, the CD40-CD40L pathway appears to be of major importance, as demonstrated by the induction of tolerance following disruption of this receptor-ligand interaction. 4 The subsequent molecular mechanisms controlling APC function in tolerance and immunity are poorly defined. The NF-kB/Rel family of proteins include 5 subunits: c-Rel, RelA, RelB, NF-kB1, and NF-kB2, which form homodimers or heterodimers. At steady state, most of these proteins are inactive within the cytoplasm, bound by inhibitory IkB proteins. Activation by the classical pathway within a broad range of cells (including APCs and T cells) occurs as a result of a variety of membrane signals, including TNF, IL-1, and Toll receptors, that allow nuclear import of c-Rel and RelA heterodimers with subsequent transcriptional activation of inflammatory proteins. Activation by the alternative pathway within APCs is the result of lymphocyte interactions and signaling through the lymphotoxin-␤ receptor, BAFF receptor or CD40, resulting in nuclear import of p52/RelB heterodimers and transcriptional activation of characterized and uncharacterized proteins that result in maturation and antigenpresenting activity within professional APCs. [5][6][7] Because APCs are known to be critical for the initiation and maintenance of GVHD 8,9 and their activation occurs rapidly after transplantation, 10 we hypothesized that maintaining host APCs in a state of RelB inactivity during conditioning would promote the induction of peripheral tolerance after allogeneic stem cell transplantation (SCT). We found that the lack of RelB within either host or donor APCs l...

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Reentry of T cells to the adult thymus is restricted to activated T cells.

Cited by 248 publications

References 23 publications

Induction of Central Tolerance by Mature T Cells

Induction of Central Tolerance by Mature T Cells

Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

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Reentry of T cells to the adult thymus is restricted to activated T cells.

Cited by 248 publications

References 23 publications

Induction of Central Tolerance by Mature T Cells

Induction of Central Tolerance by Mature T Cells

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD

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Increased numbers of thymic and peripheral CD4⁺ CD25⁺Foxp3⁺ cells in the absence of CD5 signaling