Effector T lymphocyte line cells migrate to the thymus and persist there

Naparstek, Yaakov; Holoshitz, Joseph; Eisenstein, Steven; Reshef, Tamara; Rappaport, Sara; Chemke, Juan; Ben‐Nun, Avraham; Cohen, Irun R.

doi:10.1038/300262a0

Cited by 149 publications

(78 citation statements)

References 16 publications

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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: 94%

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

confidence: 94%

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

et al. 2009

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“…Several recent publications have suggested that CD3, CD4 and CD8 may be lost from the cell surface of human T cells upon activation in vitro (4)(5)(6)(7)(8)(9). Since T cells have been reported to be capable of returning to the thymus from the secondary lymphoid organs (10), this raises questions about the source of the minor subpopulations of double negative cells in the thymus (11,12). Are they all immature cells or are some activated mature T cells?…”

Section: Introductionmentioning

confidence: 99%

The surface phenotype of activated T lymphocytes

1988

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Summary The surface phenotype of T cells reflects both their relative maturity and their activation slate. To determine the pattern of surface markers characteristic of activated T cells, purified mature T cells were stimulated in vitro for periods of 0-5-5 days with Concanavalin-A (Con-A) or phorbol myristic acetate (PMA) and ionomycin, fluorescein-labelled with monoclonal antibodies, then analysed by flow cytometry. The level of expression of the function-associated antigens CD4 (L3T4) and CD8 (Ly-2) decreased transiently early after activation with PMA/ionomycin, but not after stimulation with Con-A. Both stimuli caused a small drop in the level of CD3 and the T cell antigen receptor (TCR). At no time was CD3, CD4 or CD8 completely lost from the surface. Following activation Pgp-1, the interleukin-2 (IL-2) receptor (as detected by the monoclonal antibody 7D4) and the peanut agglutinin (PNA) receptor were gained by a proportion of cells, MEL-14 was lost by a proportion of cells, and no change was observed in the expression of heat stable antigen. Thy-1 or Ly-1. From the present data no evidence has been found for the generation of the 'immature', CD4~ CD8" phenotype found in the thymus by activation of mature T cells. During T cell development, however, changes in expression of Pgp-1, MEL-14, the IL-2 receptor and the PNA receptor may be associated with activation, rather than diiferentiation per se.

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“…As discussed earlier (see Introduction), passive transfer of self antigens into the thymus might serve to promote self tolerance induction . It is notable that autoreactive T cells can return to the thymus after activation in the periphery (3,4). Such homing could be a device to inhibit the further production of T cells with similar self specificity; the blasts might carry MHC/self antigen complexes (see references 22 and 23) into the thymus and display these complexes to newly formed T cells in tolerogenic form.…”

Section: Migration Of T Blasts To the Thymusmentioning

confidence: 99%

“…This notion rests on the assumption that lymphocyte traffic from the thymus is strictly unidirectional . However, there are a number of reports that T cell lines or mature lymphocytes harvested from the secondary lymphoid organs are able to localize in the thymus in appreciable numbers after intravenous injection (3)(4)(5)(6) . These cells localize largely in the medulla .…”

mentioning

confidence: 99%

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

Agus

Surh

Sprent

1991

The Journal of Experimental Medicine

248

165

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SummaryTo seek information on the capacity of mature T cells to migrate to the thymus, mice were injected with Thy-l-marked populations enriched for resting T cells or T blast cells ; localization of the donor cells in the host thymus was assessed by staining cryostat sections of thymus and by FACS® analysis of cell suspensions . With injection of purified resting T cells, thymic homing was extremely limited, even with injection of large doses of cells. By contrast, in vivo generated T blast cells migrated to the thymus in substantial numbers . Thymic homing by T blasts was >50-fold more efficient than with resting T cells . Blast cells localized largely in the medulla and remained in the thymus for at least 1 mo post-transfer. Interestingly, localization of T blasts in the thymus was 10-fold higher in irradiated hosts than normal hosts . Thymic homing was especially prominent in mice injected with T blasts incubated in vitro with the DNA precursor, 125 I-5-iodo-2'deoxyuridine ( 125IDUR); with transfer of 125IDURlabeled blasts to irradiated hosts, up to 5% of the injected counts localized in the host thymus. These data suggest that thymic homing by T blasts might be largely restricted to cells in S phase. The physiological significance of blast cell entry to the thymus is unclear. The possibility that these cells participate in intrathymic tolerance induction is discussed.

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Effector T lymphocyte line cells migrate to the thymus and persist there

Cited by 149 publications

References 16 publications

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

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

The surface phenotype of activated T lymphocytes

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

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Effector T lymphocyte line cells migrate to the thymus and persist there

Cited by 149 publications

References 16 publications

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

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

The surface phenotype of activated T lymphocytes

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

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

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