CD4+/CD25+ Regulatory Cells Inhibit Activation of Tumor-Primed CD4+ T Cells with IFN- -Dependent Antiangiogenic Activity, as well as Long-Lasting Tumor Immunity Elicited by Peptide Vaccination (original) (raw)
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Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells
European Journal of Immunology, 2002
Anergic/suppressive CD4 + CD25 + T cells have been proposed to play an important role in the maintenance of peripheral tolerance. Here we demonstrate that in humans these cells suppress proliferation to self antigens, but also to dietary and foreign antigens. The suppressive CD4 + CD25 + T cells display a broad usage of the T cell receptor V g repertoire, suggesting that they recognize a wide variety of antigens. They reside in the primed/memory CD4 + CD45RO + CD45RB low subset and have short telomeres, indicating that these cells have the phenotype of highly differentiated CD4 + T cells that have experienced repeated episodes of antigen-specific stimulation in vivo. This suggests that anergic/suppressive CD4 + CD25 + T cells may be generated in the periphery as a consequence of repeated antigenic encounter. This is supported by the observation that highly differentiated CD4 + T cells can be induced to become anergic/suppressive when stimulated by antigen presented by non-professional antigen-presenting cells. We suggest that besides being generated in the thymus, CD4 + CD25 + regulatory T cells may also be generated in the periphery. This would provide a mechanism for the generation of regulatory cells that induce tolerance to a wide array of antigens that may not be encountered in the thymus.
CD4+CD25+ T cells as immunoregulatory T cells in vitro
European Journal of Immunology, 2002
We have further characterized the in vitro phenotype and function of anergic and suppressive CD4 + 25 + T cells. Following TCR ligation, DO.11.10 CD4 + 25 + T cells suppress the activation of OT-1 CD8 + 25 -T cells in an antigen nonspecific manner. Although suppression was seen when using a mixture of APC from both parental strains, it was very much more marked when using F1 APC. APC pretreated with, and then separated from CD4 + 25 + T cells did not have diminished T cell costimulatory function, suggesting that APC are not the direct targets of CD4 + 25 + T cell regulation. CTLA-4 blockade failed to abrogate suppression by CD4 + 25 + T cells in mixing experiments. Although CD4 + 25 + T cells failed to respond following crosslinking of TCR, they could be induced to proliferate following the addition of exogenous IL-2, allowing the generation of a T cell line from CD4 + 25 + T cells. After the first in vitro restimulation, CD4 + 25 + T cells were still anergic and suppressive following TCR engagement. However, after three rounds of restimulation, their anergic and suppressive status was abrogated.
CD4-mediated functional activation of human CD4+CD25+ regulatory T cells
European Journal of Immunology, 2007
Naturally occurring CD4 + CD25 + FoxP3 + regulatory T cells (CD25 + Tregs) constitute a specialized population of T cells that is essential for the maintenance of peripheral selftolerance. The immune regulatory function of CD25 + Tregs depends upon their activation. We found that anti-CD4 antibodies activate the suppressive function of human CD25 + Tregs in a dose-dependent manner. We demonstrate that CD4-activated CD25 + Tregs suppress the proliferation of CD4 + and CD8 + T cells, their IL-2 and IFN-c production as well as the capacity of CD8 + T cells to re-express CD25. By contrast, anti-CD4 stimulation did not induce suppressive activity in conventional CD4 + T cells. These results identify CD4 as a trigger for the suppressive function of CD25 + Tregs and suggest a possible CD4-mediated exploitation of these cells.
CD4+ CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2
2005
CD4 + CD25 + T regulatory (T reg) cells control immunologic tolerance to self-antigens and play a role in suppressing antitumor immune responses, but the mechanism of suppression in vivo remains uncertain. Recently, signaling through the high-affinity interleukin-2 (IL-2) receptor has been shown to be critical for T reg cell differentiation and survival in vivo. Mice deficient in IL-2 or its receptor (CD25 or CD122) or deficient in downstream signaling molecules, including JAK-3 and STAT-5, do not develop a stable population of T reg cells and subsequently acquire lymphoproliferative disease and autoimmunity. in vitro, IL-2 is required to expand T reg cells and to induce their suppressive characteristics. Conversely, IL-2-based regimens can activate cellular antitumor immunity and are the mainstay of immunotherapies directed against melanoma and kidney cancers. Given the seemingly disparate effects of IL-2, the authors discuss the possibility that IL-2 may not be the optimal T-cell growth factor in vivo, but rather an inducer of self-tolerance. The authors propose that other γ c-signaling cytokines, including IL-15, may be alternative choices for the immunotherapy of cancer.
Suppression of CD4+ T Lymphocyte Effector Functions by CD4+CD25+ Cells In Vivo
The Journal of Immunology, 2004
CD4 ؉ CD25 ؉ regulatory T cells have been extensively studied during the last decade, but how these cells exert their regulatory function on pathogenic effector T cells remains to be elucidated. Naive CD4 ؉ T cells transferred into T cell-deficient mice strongly expand and rapidly induce inflammatory bowel disease (IBD). Onset of this inflammatory disorder depends on IFN-␥ production by expanding CD4 ؉ T cells. Coinjection of CD4 ؉ CD25 ؉ regulatory T cells protects recipient mice from IBD. In this study, we show that CD4 ؉ CD25 ؉ regulatory T cells do not affect the initial activation/proliferation of injected naive T cells as well as their differentiation into Th1 effectors. Moreover, naive T cells injected together with CD4 ؉ CD25 ؉ regulatory T cells into lymphopenic hosts are still able to respond to stimuli in vitro when regulatory T cells are removed. In these conditions, they produce as much IFN-␥ as before injection or when injected alone. Finally, when purified, they are able to induce IBD upon reinjection into lymphopenic hosts. Thus, prevention of IBD by CD4 ؉ CD25 ؉ regulatory T cells is not due to deletion of pathogenic T cells, induction of a non reactive state (anergy) among pathogenic effector T cells, or preferential induction of Th2 effectors rather than Th1 effectors; rather, it results from suppression of T lymphocyte effector functions, leading to regulated responses to self.
European Journal of Immunology, 2002
Although it is known that the immune system can mount responses to a variety of tumors it is clear that most tumors exhibit weak or even undetectable immunogenicity. Recent findings suggest that the lack of tumor immunogenicity is partly due to a population of cells called CD4 + CD25 + regulatory T cells since depletion of these cells in mice can result in tumor rejection. These cells have also been shown to inhibit the development of organ-specific autoimmune diseases suggesting that they inhibit immune responses to tissue-specific selfantigens. Such immune responses may also mediate tumor rejection. Alternatively, immune responses in mice depleted of regulatory cells may target tumor antigens that are not tissuespecific, but which are shared by tumors of diverse origins. In experiments performed to discriminate between these possibilities we found, using the murine colorectal tumor CT26, that tumor immunity stimulated in the absence of regulatory cells is not restricted to tumors of colorectal origin, but is effective against tumors of different histological types such as B cell lymphomas and a renal cell carcinoma. By comparing this to CT26-induced immunity through the use of adjuvant we show that the generation of cross-reactive tumor immunity is a specific manifestation of CD25 + regulatory cell depletion. The generation of CD4 + T cells capable of mediating tumor rejection is another important feature of tumor immunity induced in the absence of CD25 + cells.
Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo
Journal of Experimental Medicine, 2003
The failure of CD25 ϩ regulatory T cells (T regs ) to proliferate after T cell receptor (TCR) stimulation in vitro has lead to their classification as naturally anergic. Here we use T regs expressing a transgenic TCR to show that despite anergy in vitro, T regs proliferate in response to immunization in vivo. T regs also proliferate and accumulate locally in response to transgenically expressed tissue antigen whereas their CD25 Ϫ counterparts are depleted at such sites. Collectively, these data suggest that the anergic state that characterizes CD25 ϩ T regs in vitro may not accurately reflect their responsiveness in vivo. These observations support a model in which T reg population dynamics are shaped by the local antigenic environment.