Differential response of murine CD4+CD25+ and CD4+CD25– T cells to dexamethasone‐induced cell death

Chen, Xin; Murakami, Takaya; Oppenheim, Joost J.; Howard, O. M. Zack

doi:10.1002/eji.200324506

Cited by 181 publications

(128 citation statements)

References 43 publications

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“…The particular effect of DEX on Treg expansion is consistent with prior findings by Chen et al that DEX alone could alter the ratio of CD4 ϩ CD25 ϩ Treg to CD4 ϩ CD25 Ϫ conventional T cells in vivo in favor of the former (16) and that DEX could also amplify IL-2-dependent expansion of functional CD4 ϩ CD25 ϩ Foxp3 ϩ Treg in vivo (17). The novel finding from the present study is that when combined with antigenic immunization, the use of DEX can lead to preferential induction of Treg that are Ag-specific and long-term persistent.…”

Section: Resultssupporting

confidence: 90%

Cutting Edge: Immunosuppressant as Adjuvant for Tolerogenic Immunization

Kang

Wang

et al. 2008

The Journal of Immunology

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Vaccination for autoimmune and alloimmune diseases has long been an attractive idea. Yet, there is no suitable adjuvant to forcefully steer the immune response toward tolerance. In this study we show that dexamethasone, a potent glucocorticoid immunosuppressant, can function as a tolerogenic adjuvant when applied together with peptide immunogen. BALB/c mice with pre-established delayed-type hypersensitivity to hen OVA were immunized with an OVA-derived, MHC II-restricted peptide (OVA323–339) in the presence of dexamethasone. The treatment caused long-term desensitization in treated animals to hen OVA via a dexamethasone-dependent tolerogenic mechanism that blocks maturation of dendritic cells and expands OVA323–339-specific CD4+CD25+Foxp3+ regulatory T cells in vivo. Similar treatment of NOD mice using dexamethasone and an insulin-derived, MHC II-restricted peptide (B:9–23) prevented predisposed spontaneous diabetes. Remarkably, in both models, dexamethasone-augmented immunization induced long-term persistent, Ag-specific regulatory T cells responsive to recall Ags. These results reveal for the first time the potential usefulness of immunosuppressants as tolerogenic adjuvants.

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Section: Resultssupporting

confidence: 90%

Cutting Edge: Immunosuppressant as Adjuvant for Tolerogenic Immunization

Kang

Wang

et al. 2008

The Journal of Immunology

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“…This observation is consistent with the increased resistance of CD4 1 CD25 1 Foxp3 1 Treg cells to other cell death-inducing reagents such as dexamethasone and anti-CD4-depleting mAb relative to CD4 1 CD25 2 T effector cells, as recently reported. 33,45 The molecular mechanisms for the differential responses of murine CD4 1 CD25 1 Foxp3 1 Treg and CD4 1 CD25 2 T cells to cell death may be related to the distinguished expression levels of anti-apoptosis Consistent with the observation in naive mice, 2-Gy WBI significantly increased the proportion of CD4 1 CD25 1 Foxp3 1 Treg cells in the periphery of mouse recipients of allogeneic BMCs. WBI is widely used for mixed chimera establishment and other transplant settings to deplete immune and hematopoietic cells and make space.…”

Section: Discussionmentioning

confidence: 62%

2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

Zhang

Liu

et al. 2010

Cell Mol Immunol

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CD4 1 CD25 1 T regulatory (Treg) cells are critical in inducing and maintaining immunological self-tolerance as well as transplant tolerance. The effect of low doses of whole-body irradiation (WBI) on CD4 1 CD25 1 Foxp3 1 Treg cells has not been determined. The proportion, phenotypes and function of CD4 1 CD25 1 Treg cells were investigated 0.5, 5 and 15 days after euthymic, thymectomized or allogeneic bone marrow transplanted C57BL/6 mice received 2-Gy c-rays of WBI. The 2-Gy WBI significantly enhanced the ratios of CD4 1 CD25 1 Treg cells and CD4 1 CD25 1 Foxp3 1 Treg cells to CD4 1 T cells in peripheral blood, lymph nodes, spleens and thymi of mice. The CD4 1 CD25 1 Treg cells of the WBI-treated mice showed immunosuppressive activities on the immune response of CD4 1 CD25 2 T effector cells to alloantigens or mitogens as efficiently as the control mice. Furthermore, 2-Gy c-ray WBI significantly increased the percentage of CD4 1 CD25 1 Foxp3 1 Treg cells in the periphery of either thymectomized mice or allogeneic bone marrow transplanted mice. The in vitro assay showed that ionizing irradiation induced less cell death in CD4 1 CD25 1 Foxp3 1 Treg cells than in CD4 1 CD25 2 T cells. Thus, a low dose of WBI could significantly enhance the level of functional CD4 1 CD25 1 Foxp3 1 Treg cells in the periphery of naive or immunized mice. The enhanced proportion of CD4 1 CD25 1 Foxp3 1 Treg cells in the periphery by a low dose of WBI may make hosts more susceptible to immune tolerance induction.

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“…This strategy will prove to be useful in autoimmune conditions wherein it is beneficial to the host if T reg cells can more actively inhibit the functioning of autoreactive T cells. Moreover, administration of dexamethasone, an immunosuppressive glucocorticoid, into wild type BALB/c mice led to less CD4 + CD25 + T cell death compared to the CD4 + CD25 − T cell apoptosis (22). In this context, we show here that CD5, a cell surface receptor expressed on T cells is influential in regulating the suppressive nature of T reg cells in an in vitro cell co-culture system.…”

Section: Introductionmentioning

confidence: 66%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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Differential response of murine CD4⁺CD25⁺ and CD4⁺CD25^– T cells to dexamethasone‐induced cell death

Abstract: + T regulatory cells, and this property may contribute to the anti-inflammatory and immunosuppressive efficacy of glucocorticoids. Our data also suggest that selective protection of CD4 + CD25+ T cell from apoptosis may constitute a role in immune tolerance for IL-2.

Cited by 181 publications

References 43 publications

Cutting Edge: Immunosuppressant as Adjuvant for Tolerogenic Immunization

Cutting Edge: Immunosuppressant as Adjuvant for Tolerogenic Immunization

2-Gy whole-body irradiation significantly alters the balance of CD4+CD25−T effector cells and CD4+CD25+Foxp3+T regulatory cells in mice

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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