Comparative Study of Regulatory T Cell Function of Human CD25+CD4+ T Cells from Thymocytes, Cord Blood, and Adult Peripheral Blood (original) (raw)
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Immunology, 2005
Activation of self-reactive T cells in healthy adults is prevented by the presence of autoantigen-specific CD4 + CD25 + regulatory T cells (CD25 + T reg ). To explore the functional development of autoantigen-reactive CD25 + T reg in humans we investigated if thymic CD25 + T reg from children aged 2 months to 11 years and cord blood CD25 + T reg are able to suppress proliferation and cytokine production induced by specific antigens. While CD4 + CD25 ) thymocytes proliferated in response to myelin oligodendrocyte glycoprotein (MOG), tetanus toxoid and beta-lactoglobulin, suppression of proliferation was not detected after the addition of thymic CD25 + T reg . However, CD25 + T reg inhibited interferon (IFN)-c production induced by MOG, which indicates that MOG-reactive CD25 + T reg are present in the thymus. In contrast, cord blood CD25 + T reg suppressed both proliferation and cytokine production induced by MOG. Both cord blood and thymic CD25 + T reg expressed FOXP3 mRNA. However, FOXP3 expression was lower in cord blood than in thymic CD25 + T cells. Further characterization of cord blood CD25 + T cells revealed that FOXP3 was highly expressed by CD25 + CD45RA + cells while CD25 + CD45RA ) cells contained twofold less FOXP3, which may explain the lower expression level of FOXP3 in cord blood CD25 + T cells compared to thymic CD25 + T cells. In conclusion, our data demonstrate that low numbers of MOG-reactive functional CD25 + T reg are present in normal thymus, but that the suppressive ability of the cells is broader in cord blood. This suggests that the CD25 + T reg may be further matured in the periphery after being exported from the thymus.
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
International Immunology, 2004
Naturally occurring CD25 1 CD4 1 regulatory T cells are engaged in the maintenance of immunological self-tolerance and down-regulation of various immune responses. Recent studies with mice showed that Foxp3, which encodes the transcription factor Scurfin, is a master regulatory gene for the development and function of CD25 1 CD4 1 regulatory T cells. Here we examined the role of FOXP3 in human CD25 1 CD4 1 regulatory T cells. The FOXP3 gene and its protein product were preferentially expressed in peripheral CD25 1 CD4 1 T cells, in particular CD25 1 CD45RO 1 CD4 1 T cells in normal individuals and, interestingly, in some human T cell leukemia virus type 1-infected T cell lines, which constitutively express CD25. TCR stimulation of CD25 ÿ CD45RO ÿ CD4 1 naive T cells failed to elicit FOXP3 expression at the gene or protein level. Ex vivo retroviral gene transfer of FOXP3, on the other hand, converted peripheral CD25 ÿ CD45RO ÿ CD4 1 naive T cells into a regulatory T cell phenotype similar to CD25 1 CD4 1 regulatory T cells. For example, FOXP3-transduced T cells exhibited impaired proliferation and production of cytokines including IL-2 and IL-10 upon TCR stimulation, up-regulated the expression of regulatory T cell-associated molecules such as CD25 and CTL-associated antigen-4 and suppressed in vitro proliferation of other T cells in a cell-cell contact-dependent manner. Thus, human FOXP3 is a crucial regulatory gene for the development and function of CD25 1 CD4 1 regulatory T cells, and can be used as their reliable marker. Furthermore, regulatory T cells de novo produced from normal naive T cells by FOXP3 transduction can be instrumental for treatment of autoimmune/ inflammatory diseases and negative control of various immune responses.
Immunology, 2010
Relatively little is known about regulatory T (Treg) cells and their functional responses in dogs. We have used the cross-reactive anti-mouse/rat Foxp3 antibody clone FJK-16s to identify a population of canine CD4+ FOXP3high T cells in both the peripheral blood (PB) and popliteal lymph node (LN). FOXP3+ cells in both PB and LN yielded positive staining with the newly developed anti-murine/human Helios antibody clone 22F6, consistent with the notion that they were naturally occurring Treg cells. Stimulation of mononuclear cells of LN origin with concanavalin A (Con A) in vitro yielded increased proportions and median fluorescence intensity of FOXP3 expression by both CD4+ and CD8+ T cells. Removal of the Con A and continued culture disclosed a CD4+ FOXP3high population, distinct from the CD4+ FOXP3intermediate T cells; very few CD8+ FOXP3high T cells were observed, though CD8+ FOXP3intermediate cells were present in equal abundance to CD4+ FOXP3intermediate cells. The CD4+ FOXP3high T cells were thought to represent activated Treg cells, in contrast to the FOXP3intermediate cells, which were thought to be a more heterogeneous population comprising predominantly activated conventional T cells. Co-staining with interferon-γ (IFN-γ) supported this notion, because the FOXP3high T cells were almost exclusively IFN-γ−, whereas the FOXP3intermediate cells expressed a more heterogeneous IFN-γ phenotype. Following activation of mononuclear cells with Con A and interleukin-2, the 5% of CD4+ T cells showing the highest CD25 expression (CD4+ CD25high) were enriched in cells expressing FOXP3. These cells were anergic in vitro, in contrast to the 20% of CD4+ T cells with the lowest CD25 expression (CD4+ CD25−), which proliferated readily. The CD4+ CD25high FOXP3high T cells were able to suppress the proliferation of responder CD4+ T cells in vitro, in contrast to the CD4+ CD25− cells, which showed no regulatory properties.