CD4+CD25+FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses (original) (raw)
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Clinical & Developmental Immunology, 2008
CD25 + CD4 + regulatory T cells suppress T cell activation and regulate multiple immune reactions in in vitro and in vivo studies. To define the regulatory function of human CD25 + CD4 + T cells at various stages of maturity, we investigated in detail the functional differences of CD25 + CD4 + T cells from thymocytes, cord blood (CB), and adult peripheral blood (APB). CB CD25 + CD4 + T cells displayed low-FOXP3 protein expression level and had no suppressive activity. In contrast, CD25 + CD4 + T cells from thymocytes or APB expressed high expression level of FOXP3 protein associated with significant suppressive activity. Although CB CD25 + CD4 + T cells exhibited no suppressive activity, striking suppressive activity was observed following expansion in culture associated with increased FOXP3 expression and a shift from the CD45RA + to the CD45RA − phenotype. These functional differences in CD25 + CD4 + T cells from Thy, CB, and APB hence suggest a pathway of maturation for Treg in the peripheral immune system.
Two Functional Subsets of FOXP3+ Regulatory T Cells in Human Thymus and Periphery
Immunity, 2008
Previous studies suggest that thymus produces a homogenous population of natural regulatory T cells (T R ) that express a transcriptional factor Foxp3 and control autoimmunity through a cell contactdependent mechanism. We found two subsets of Foxp3 + natural T R defined by ICOS-expression in the human thymus and periphery. While the ICOS + Foxp3 + T R use IL-10 to suppress dendritic cell function and TGF-β to suppress T cell function, the ICOS − Foxp3 + T R use TGF-β only. The survival and proliferation of the two subsets of T R are differentially regulated by signaling through ICOS or CD28 respectively. We suggest that the selection of natural T R in thymus is coupled with T R differentiation into two subsets imprinted with different cytokine expression potentials and use both cell-contact-dependent and independent mechanisms for immunosuppression in periphery.
Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood
Immunology, 2002
CD4 + CD25 + regulatory T cells prevent organ-specific autoimmune diseases in various animal models. We analysed human lymphoid tissues to identify similar CD25 + regulatory T cells. Adult peripheral blood contained two populations of CD4 + T cells that expressed CD25 at different densities. The larger population (<40%) expressed intermediate levels of CD25 (CD25 + ) and displayed a memory T-cell phenotype (CD45RA x /RO + , CD45RB low , CD95 + , CD62L low , CD38 low ). The smaller population of cells (<2%) expressed very high levels of CD25 (CD25 ++ ). In addition to the activation/memory T-cell antigens mentioned above they also expressed intracellular CD152 (CTLA-4) as well as enhanced levels of cell-surface CD122, similar to the murine CD4 + CD25 + regulatory counterpart. To exclude that the CD25 ++ cells had not been recently primed by external antigen we analysed cord blood and thymus. CD25 ++ , CD152 + and CD122 ++ cells were present in paediatric thymus (10% of CD4 + CD8 x thymocytes) expressing signs of recent selection (CD69 + ) and in cord blood (5% of CD4 + cells) where they showed a naive phenotype. In addition, cord blood contained a small population of CD25 + cells (<2% of CD4 T cells) that were CD152 x and CD122 low and displayed signs of activation. Together with published data that CD25 + CD25 ++ cells from the thymus and peripheral blood are regulatory, our results suggest that regulatory CD25 + T cells leave the thymus in a naïve state and become activated in the periphery.
Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes
European Journal of Immunology, 2005
Among the several mechanisms known to be involved in the establishment and maintenance of immunological tolerance, the activity of CD4 + CD25 + regulatory T lymphocytes has recently incited most interest because of its critical role in inhibition of autoimmunity and anti-tumor immunity. Surprisingly, very little is known about potential genetic modulation of intrathymic regulatory T lymphocyte-development. We show that distinct proportions of CD4 + CD25 + FoxP3 + regulatory T cells are found in thymi of common laboratory mouse strains. We demonstrate that distinct levels of phenotypically identical regulatory T cells develop with similar kinetics in the studied mice. Our experimental data on congenic mousestrains indicate that differences are not caused by the distinct MHC haplotypes of the inbred mouse strains. Moreover, the responsible loci act in a thymocyte intrinsic manner, confirming the latter conclusion. We have not found any correlation between thymic and peripheral levels of regulatory T cells, consistent with known homeostatic expansion and/or retraction of the peripheral regulatory T cell pool. Our data indicate that polymorphic genes modulate differentiation of regulatory T cells. Identification of responsible genes may reveal novel clinical targets and still elusive regulatory T cell-specific markers. Importantly, these genes may also modulate susceptibility to autoimmune-disease. Conversion of CD4+ CD25-cells into CD4+ CD25+ regulatory T cells in vivo requires B7 costimulation, but not the thymus. J Exp Med 2005. 201: 127-137. 23 Apostolou, I. and von Boehmer, H., In vivo instruction of suppressor commitment in naive T cells. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide.
Human thymus contains major dendritic cell (DC) subsets, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs). We previously showed that mDCs, educated by thymic stromal lymphopoietin (TSLP) produced by the epithelial cells of the Hassall’s corpuscles, induced differentiation of CD4+CD25− thymocytes into Forkhead Box P3+ (FOXP3+) regulatory T cells (TR) within the medulla of human thymus. In this study, we show that pDCs expressed the TSLP receptor and IL-7 receptor a complexes upon activation and became responsive to TSLP. TSLPactivated human pDCs secrete macrophage-derived chemokine CCL-22 and thymus- and activation-regulated chemokine CCL-17 but not Th1- or Th2-polarizing cytokines. TSLP-activated pDCs induced the generation of FOXP3+ TR from CD4+CD8−CD25− thymocytes, which could be strongly inhibited by Th1-polarizing cytokine IL-12 or Th2-polarizing cytokine IL-4. Interestingly, the FOXP3+ TR induced by the TSLP-pDCs expressed more IL-10 but less TGF-b than that induced by the TSLP-mDCs. These data suggest that TSLP expressed by thymic epithelial cells can activate mDCs and pDCs to positively select the FOXP3+ TR with different cytokine production potential in human thymus. The inability of TSLP to induce DC maturation without producing Th1- or Th2-polarizing cytokines may provide a thymic niche for TR development.
BMC immunology, 2006
Generation of functional (CD4+)(CD8-)CD25+ regulatory T cells (Treg) in the murine thymus depends on FoxP3. Removal of the thymus from neonatal mice has been shown to result in a multiple organ autoimmune disease phenotype that can be prevented by introducing the FoxP3+ Treg population to the animal. It has therefore, been proposed that functional FoxP3+ Treg cells are not made in the neonatal thymus; however, it remains unclear when and where functional (FoxP3+)(CD4+)(CD8-)CD25+ thymocytes are generated in postnatal thymus. We report that neither FoxP3 mRNA nor protein is expressed in (CD4+)(CD8-)CD25+, or (CD4+)(CD8-)CD25- thymocytes until 3-4 days post birth, despite the presence of mature (CD4+)(CD8-)CD25+/- thymocytes in the thymus by 1-2 days after birth. (FoxP3-)(CD4+)(CD8-)CD25+ thymocytes from day 2 newborn mice show no Treg activity. Interestingly, we are able to detect low numbers of FoxP3+ thymocytes dispersed throughout the medullary region of the thymus as early as 3-4...