The Experts below are selected from a list of 315 Experts worldwide ranked by ideXlab platform
Ethan M Shevach - One of the best experts on this subject based on the ideXlab platform.
-
cd4 CD5 regulatory t cells render naive cd4 cd25 t cells anergic and suppressive
Immunology, 2007Co-Authors: Miao Qiao, Angela M Thornton, Ethan M ShevachAbstract:CD4(+) CD25(+) Foxp3(+) naturally occurring regulatory T cells (nTreg) are potent inhibitors of almost all immune responses. However, it is unclear how this minor population of cells is capable of exerting its powerful suppressor effects. To determine whether nTreg mediate part of their suppressor function by rendering naive T cells anergic or by converting them to the suppressor phenotype, we cocultured mouse nTreg with naive CD4(+) CD25(-) T cells from T-cell receptor (TCR) transgenic mice on a RAG deficient (RAG(-/-)) background in the presence of anti-CD3 and interleukin-4 (IL-4) to promote cell viability. Two distinct responder cell populations could be recovered from the cocultures. One population remained undivided in the coculture and was non-responsive to restimulation with anti-CD3 or exogenous IL-2, and could not up-regulate IL-2 mRNA or CD25 expression upon TCR restimulation. Those responder cells that had divided in the coculture were anergic to restimulation with anti-CD3 but responded to restimulation with IL-2. The undivided population was capable of suppressing the response of fresh CD4(+) CD25(-) T cells and CD8(+) T cells, while the divided population was only marginally suppressive. Although cell contact between the induced regulatory T cell (iTreg) and the responders was required for suppression to be observed, anti-transforming growth factor-beta partially abrogated their suppressive function. The iTreg did not express Foxp3. Therefore nTreg are not only able to suppress immune responses by inhibiting cytokine production by CD4(+) CD25(-) responder cells, but also appear to modulate the responder cells to render them both anergic and suppressive.
-
activation requirements for the induction of cd4 cd25 t cell suppressor function
European Journal of Immunology, 2004Co-Authors: Angela M Thornton, Ciriaco A Piccirillo, Ethan M ShevachAbstract:The in vivo differentiation/survival of CD4+CD25+ T suppressor cells is dependent on IL-2 and CD28-mediated costimulatory signals. To determine the cytokine and costimulatory requirements for CD25+ T cells in vitro, we established a two-stage culture system where CD25+ T cells were activated in a primary culture. In the subsequent culture, activated CD4+CD25+ cells were then mixed with responders in order to assess their suppressor function. Pre-culture of CD25+ T cells with anti-CD3 alone resulted in poor survival and minimal induction of suppressor activity. Pre-culture in the presence of anti-CD3 and IL-2 or IL-4, but not IL-6, IL-7, IL-9, IL-10 or IL-15, resulted in proliferation of the CD25+ cells and induction of potent suppressor function. Inhibition of the interaction of CD28 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with CD80/CD86 in the pre-culture of CD4+CD25+ cells did not prevent the induction of suppressor function. Furthermore, the inhibition of costimulatory signals did not inhibit the ability of fresh CD25+ T cells to inhibit CD8+ responders under conditions where activation of the responders was independent of CD80/CD86. These studies support the view that activation of CD25+ T cells requires IL-2/IL-4 for their survival/differentiation into effector cells, but is independent of CD28/CTLA-4-mediated costimulation.
G Stingl - One of the best experts on this subject based on the ideXlab platform.
-
Phenotypic changes that TCR V gamma 3+ fetal thymocytes undergo during their maturation into dendritic epidermal T cells.
The Journal of investigative dermatology, 1995Co-Authors: E Payer, R Kutil, G StinglAbstract:Murine Thy-1+, TCR V gamma 3/V delta 1+ dendritic epidermal T cells (DETC) express CD2 antigens, but differ from most other T-cell subsets in their absence of CD4, CD5, and CD8 antigens. To determine whether negativity for those antigens is an intrinsic feature of a given T-cell population or whether such triple-negative T cells go through a maturational stage during which they express these antigens, we determined the phenotype of TCR V gamma 3+ fetal thymocytes, which are the precursor cells of DETC. We found that TCR V gamma 3+ fetal thymocytes at day 17 of gestation are CD2+, CD5+, mostly CD8+, and partly CD4+. The expression of CD5 is highest on early TCR V gamma 3+ thymocytes; these cells express intermediate levels of CD5 when they leave the thymus and lose CD5 expression until or shortly after arrival in the epidermis. A similar loss of CD5 expression by TCR V gamma 3+ cells was observed in vitro under various culture conditions. To determine whether expression of CD5 is important for the maturation of DETC, we searched for these cells in the epidermis of CD5-deficient mice. There was no alteration in the number of Thy-1+/TCR V gamma 3+ dendritic cells in the epidermis of CD5-/- mice. Even though the latter finding speaks against a pivotal role of CD5 during the maturation of DETC, the described cell system may serve as a useful tool in further experiments aimed to clarify the function of the CD5 glycoprotein as well as the mechanism(s) regulating its expression.
-
Phenotypic Changes That TCR Vγ3+ Fetal Thymocytes Undergo During Their Maturation into Dendritic Epidermal T Cells
Journal of Investigative Dermatology, 1995Co-Authors: E Payer, R Kutil, G StinglAbstract:Murine Thy-1 + , TCR Vγ3/V*delta;1 + dendritic epidermal T cells (DETC) express CD2 antigens, but differ from most other T-cell subsets in their absence of CD4, CD5, and CD8 antigens. To determine whether negativity for those antigens is an intrinsic feature of a given T-cell population or whether such triple-negative T cells go through a maturational stage during which they express these antigens, we determined the phenotype of TCR Vγ3 + fetal thymocytes, which are the precursor cells of DETC. We found that TCR Vγ3 + fetal thymocytes at day 17 of gestation are CD2 + , CD5 + , mostly CD8 + , and partly CD4 + . The expression of CD5 is highest on early TCR Vγ3 + thymocytes; these cells express intermediate levels of CD5 when they leave the thymus and lose CD5 expression until or shortly after arrival in the epidermis. A similar loss of CD5 expression by TCR Vγ3 + cells was observed in vitro under various culture conditions. To determine whether expression of CD5 is important for the maturation of DETC, we searched for these cells in the epidermis of CD5-deficient mice. There was no alteration in the number of Thy-1 + /TCR Vγ3 + dendritic cells in the epidermis of CD5 -/- mice. Even though the latter finding speaks against a pivotal role of CD5 during the maturation of DETC, the described cell system may serve as a useful tool in further experiments aimed to clarify the function of the CD5 glycoprotein as well as the mechanism(s) regulating its expression. J Invest Dermatol 105:54S-57S, 1995
-
demonstration of a cd3 lymphocyte subset in the epidermis of athymic nude mice evidence for t cell receptor diversity
Journal of Immunology, 1992Co-Authors: E Payer, R Kutil, Robert Strohal, Adelheid Elbe, G StinglAbstract:The existence of CD3/TCR-bearing lymphocytes in athymic and thymectomized chimeric mice implies that T cell maturation can occur in the absence of a thymus. Considering the possibility that the epidermis may be one of the organs providing T cell educating stimuli, we attempted to characterize the Thy-1+ epidermal lymphocyte population of athymic mice. Immunohistologic studies of epidermal sheets revealed (1) that Thy-1+ epidermal cells of C57BL/6 nu/nu mice are CD5-, CD4-, and predominantly CD8-, and (2) that a minor subset of these cells displays anti-CD3 epsilon reactivity. Although these CD3+ epidermal cells could hardly be detected at 6 wk of age, they comprised approximately 2% of all Thy-1+ epidermal cells in 12-mo-old athymic mice. Most of these CD3+ cells expressed TCR-gamma/delta, but TCR-alpha/beta+ cells were also present. TCR-gamma/delta+ epidermal T cells of athymic mice preferentially expressed TCR V gamma 2, V gamma 4, and V gamma 5 specificities rather than TCR V gamma 3 as found on DETC of euthymic mice. Using mitogenic stimuli, we have succeeded in establishing cell lines and clones from BALB/c nu/nu and C57BL/6 nu/nu epidermis. Their marker profile corresponds to that seen on resident CD3+ epidermal cells, as well as on a very small subset of CD3+ splenic and lymph node lymphocytes of athymic mice. The ontogenetic relationship, if any, between the epidermal and lymphoid CD3+, CD5-, CD4-, CD8- cells, has yet to be clarified. Cell lines/clones representative of resident CD3+ epidermal cells of nu/nu mice should provide a useful tool in the elucidation of homing patterns and functional properties of extrathymically matured T cells.
Angela M Thornton - One of the best experts on this subject based on the ideXlab platform.
-
cd4 CD5 regulatory t cells render naive cd4 cd25 t cells anergic and suppressive
Immunology, 2007Co-Authors: Miao Qiao, Angela M Thornton, Ethan M ShevachAbstract:CD4(+) CD25(+) Foxp3(+) naturally occurring regulatory T cells (nTreg) are potent inhibitors of almost all immune responses. However, it is unclear how this minor population of cells is capable of exerting its powerful suppressor effects. To determine whether nTreg mediate part of their suppressor function by rendering naive T cells anergic or by converting them to the suppressor phenotype, we cocultured mouse nTreg with naive CD4(+) CD25(-) T cells from T-cell receptor (TCR) transgenic mice on a RAG deficient (RAG(-/-)) background in the presence of anti-CD3 and interleukin-4 (IL-4) to promote cell viability. Two distinct responder cell populations could be recovered from the cocultures. One population remained undivided in the coculture and was non-responsive to restimulation with anti-CD3 or exogenous IL-2, and could not up-regulate IL-2 mRNA or CD25 expression upon TCR restimulation. Those responder cells that had divided in the coculture were anergic to restimulation with anti-CD3 but responded to restimulation with IL-2. The undivided population was capable of suppressing the response of fresh CD4(+) CD25(-) T cells and CD8(+) T cells, while the divided population was only marginally suppressive. Although cell contact between the induced regulatory T cell (iTreg) and the responders was required for suppression to be observed, anti-transforming growth factor-beta partially abrogated their suppressive function. The iTreg did not express Foxp3. Therefore nTreg are not only able to suppress immune responses by inhibiting cytokine production by CD4(+) CD25(-) responder cells, but also appear to modulate the responder cells to render them both anergic and suppressive.
-
activation requirements for the induction of cd4 cd25 t cell suppressor function
European Journal of Immunology, 2004Co-Authors: Angela M Thornton, Ciriaco A Piccirillo, Ethan M ShevachAbstract:The in vivo differentiation/survival of CD4+CD25+ T suppressor cells is dependent on IL-2 and CD28-mediated costimulatory signals. To determine the cytokine and costimulatory requirements for CD25+ T cells in vitro, we established a two-stage culture system where CD25+ T cells were activated in a primary culture. In the subsequent culture, activated CD4+CD25+ cells were then mixed with responders in order to assess their suppressor function. Pre-culture of CD25+ T cells with anti-CD3 alone resulted in poor survival and minimal induction of suppressor activity. Pre-culture in the presence of anti-CD3 and IL-2 or IL-4, but not IL-6, IL-7, IL-9, IL-10 or IL-15, resulted in proliferation of the CD25+ cells and induction of potent suppressor function. Inhibition of the interaction of CD28 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with CD80/CD86 in the pre-culture of CD4+CD25+ cells did not prevent the induction of suppressor function. Furthermore, the inhibition of costimulatory signals did not inhibit the ability of fresh CD25+ T cells to inhibit CD8+ responders under conditions where activation of the responders was independent of CD80/CD86. These studies support the view that activation of CD25+ T cells requires IL-2/IL-4 for their survival/differentiation into effector cells, but is independent of CD28/CTLA-4-mediated costimulation.
Theresa L Whiteside - One of the best experts on this subject based on the ideXlab platform.
-
a unique subset of cd4 cd25highfoxp3 t cells secreting interleukin 10 and transforming growth factor β1 mediates suppression in the tumor microenvironment
Clinical Cancer Research, 2007Co-Authors: Laura Strauss, Christoph Bergmann, Miroslaw J Szczepanski, William E Gooding, Jonas T Johnson, Theresa L WhitesideAbstract:Purpose: Immunosuppression, including that mediated by CD4 + CD25 high Foxp3 + regulatory T cells (Treg), is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Tregs with a distinct phenotype in tumor-infiltrating lymphocytes (TIL) contribute to local immune suppression. Experimental Design: The frequency and phenotype of Treg in TIL and/or peripheral blood mononuclear cells (PBMC) in 15 HNSCC patients and PBMC in 15 normal controls were compared. Single-cell sorted CD4 + CD25 high T cells were tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidyl ester–labeled and activated autologous CD4 + CD25 − responder T cells. Transwell inserts separating Treg from responders and neutralizing interleukin-10 (IL-10) or transforming growth factor-β1 (TGF-β1) antibodies were used to evaluate the mechanisms used by Treg to suppress responder cell proliferation. Results: In TIL, CD25 + cells were enriched in the CD3 + CD4 + subset (13 ± 3%) relative to circulating CD3 + CD4 + T cells (3 ± 0.7%) in HNSCC patients ( P ≤ 0.01) or normal controls (2 ± 1.5%; P ≤ 0.001). Among the CD3 + CD4 + subset, CD25 high Treg represented 3 ± 0.5% in TIL, 1 ± 0.3% in PBMC, and 0.4 ± 0.2% in normal controls. Tregs in TIL were GITR + , IL-10 + , and TGF-β1 + , although circulating Treg up-regulated CD62L and CCR7 but not GITR, IL-10, or TGF-β1. Treg in TIL mediated stronger suppression ( P ≤ 0.001) than Treg in PBMC of HNSCC patients. The addition of neutralizing IL-10 and TGF-β antibodies almost completely abrogated suppression (5 ± 2.51%). Transwell inserts partly prevented suppression (60 ± 5% versus 95 ± 5%). Conclusions: Suppression in the tumor microenvironment is mediated by a unique subset of Treg, which produce IL-10 and TGF-β1 and do not require cell-to-cell contact between Treg and responder cells for inhibition.
Pilar Portolés - One of the best experts on this subject based on the ideXlab platform.
-
Characteristics of TCR/CD3 complex CD3ɛ chains of regulatory CD4+ T (Treg) lymphocytes: role in Treg differentiation in vitro and impact on Treg in vivo
Journal of leukocyte biology, 2013Co-Authors: José M. Rojo, Gloria Ojeda, Yenny Y. Acosta, María Montes-casado, Gabriel Criado, Pilar PortolésAbstract:Tregs are anergic CD4(+)CD25(+)Foxp3(+) T lymphocytes exerting active suppression to control immune and autoimmune responses. However, the factors in TCR recognition underlying Treg differentiation are unclear. Based on our previous data, we hypothesized that Treg TCR/CD3 antigen receptor complexes might differ from those of CD4(+)CD25(-) Tconv. Expression levels of TCR/CD3, CD3e,ζ chains, or other molecules involved in antigen signaling and the characteristics of CD3e chains were analyzed in thymus or spleen Treg cells from normal mice. Tregs had quantitative and qualitatively distinct TCR/CD3 complexes and CD3e chains. They expressed significantly lower levels of the TCR/CD3 antigen receptor, CD3e chains, TCR-ζ chain, or the CD4 coreceptor than Tconv. Levels of kinases, adaptor molecules involved in TCR signaling, and early downstream activation pathways were also lower in Tregs than in Tconv. Furthermore, TCR/CD3 complexes in Tregs were enriched in CD3e chains conserving their N-terminal, negatively charged amino acid residues; this trait is linked to a higher activation threshold. Transfection of mutant CD3e chains lacking these residues inhibited the differentiation of mature CD4(+)Foxp3(-) T lymphocytes into CD4(+)Foxp3(+) Tregs, and differences in CD3e chain recognition by antibodies could be used to enrich for Tregs in vivo. Our results show quantitative and qualitative differences in the TCR/CD3 complex, supporting the hyporesponsive phenotype of Tregs concerning TCR/CD3 signals. These differences might reconcile avidity and flexible threshold models of Treg differentiation and be used to implement therapeutic approaches involving Treg manipulation.