Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells

Stephens, Geoffrey L.; McHugh, Rebecca S.; Whitters, Matthew J.; Young, Deborah; Luxenberg, Deborah; Carreño, Beatriz M.; Collins, Mary; Shevach, Ethan M.

doi:10.4049/jimmunol.173.8.5008

Cited by 444 publications

(499 citation statements)

References 41 publications

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“…Thus, this CD4 + T cell population was associated with suppressive activity during acute FV infection. In addition, it has been reported that the treatment of FV or LP-BM5 retrovirus (which induces mouse AIDS) infected mice with an antibody against GITR, which has been suggested to either block the suppressive function of Treg cells [20], or to make CD8 + T cells refractory to Treg suppression [30], can overcome CD8 + T cell dysfunction and virusinduced immunosuppression [31,32]. Taken together, these findings indicate that CD4 + CD25 -GITR + CD103 + T cells might be an important population of induced Treg in chronic retroviral infection.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Zelinskyy¹,

Kraft²,

Schimmer³

et al. 2006

Eur J Immunol

120

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Cytolytic CD8 + T cells are critical for the control of acute Friend virus (FV) infection yet they fail to completely eliminate the virus during chronic infection because they are functionally impaired by regulatory T cells (Treg). We performed a kinetic analysis of T cell responses during FV infection to determine when dysfunction of CD8 + T cells and suppressive activity of CD4 + regulatory T cells develops. At 1 week post infection, virusspecific CD8 + T cells with effector phenotype and cytolytic potential expanded. Peak expansion was found at 12 days post infection, correlating with peak viral loads. After 2 weeks when viral loads dropped, numbers of activated CD8 + T cells started to decline. However, a population of virus-specific CD8 + T cells with effector phenotype was still detectable subsequently, but these cells had lost their ability to produce granzymes and to degranulate cytotoxic molecules. Contemporaneous with the development of CD8 + T cell dysfunction, different CD4 + T cell populations expressing cell surface markers for Treg and the Treg-associated transcription factor Foxp3 expanded. Transfer as well as depletion experiments indicated that regulatory CD4 + cells developed during the second week of FV infection and subsequently suppressed CD8 + T cell functions, which was associated with impaired virus clearance.

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Section: Discussionmentioning

confidence: 99%

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Zelinskyy¹,

Kraft²,

Schimmer³

et al. 2006

Eur J Immunol

120

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“…4A). Importantly, engagement of GITR using anti-GITR mAb (DTA-1) caused CD25 -responder T cells to escape suppression by CD25 + CD4 + T R cells as well [34] (Fig. 4B) and abrogated accumulation of ICER/CREM in T R assays to levels comparable to Fab-anti-CTLA-4 (UC-10) mAb treatment (Fig.…”

Section: Abrogation Of T R -Mediated Suppression By Ctla-4 Blockade Pmentioning

confidence: 93%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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“…A possibility is that IL-21 selectively induces on CD4 ϩ T cells specific molecules that may, in turn, antagonize the activity of CD4 ϩ CD25 ϩ T cells. A potential candidate could be the glucocorticoid-induced TNFR family-related receptor ligand, as it was recently shown that such a protein can be also expressed by T cells and provide signals that make CD4 ϩ CD25 Ϫ T cells resistant to CD25 ϩ T cell-mediated suppression (22). Studies are now in progress to address this issue.…”

Section: Discussionmentioning

confidence: 99%

IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes

Peluso

Fantini

Fina

et al. 2007

The Journal of Immunology

266

208

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High expression of IL-21 and/or IL-21R has been described in T cell-mediated inflammatory diseases characterized by defects of counterregulatory mechanisms. CD4+CD25+ regulatory T cells (Treg) are a T cell subset involved in the control of the immune responses. A diminished ability of these cells to inhibit T cell activation has been documented in immune-inflammatory diseases, raising the possibility that inflammatory stimuli can block the regulatory properties of Treg. We therefore examined whether IL-21 controls CD4+CD25+ T cell function. We demonstrate in this study that IL-21 markedly enhances the proliferation of human CD4+CD25− T cells and counteracts the suppressive activities of CD4+CD25+ T cells on CD4+CD25− T cells without affecting the percentage of Foxp3+ cells or survival of Treg. Additionally, CD4+CD25+ T cells induced in the presence of IL-21 maintain the ability to suppress alloresponses. Notably, IL-21 enhances the growth of CD8+CD25− T cells but does not revert the CD4+CD25+ T cell-mediated suppression of this cell type, indicating that IL-21 makes CD4+ T cells resistant to suppression rather than inhibiting CD4+CD25+ T cell activity. Finally, we show that IL-2, IL-7, and IL-15, but not IL-21, reverse the anergic phenotype of CD4+CD25+ T cells. Data indicate that IL-21 renders human CD4+CD25− T cells resistant to Treg-mediated suppression and suggest a novel mechanism by which IL-21 could augment T cell-activated responses in human immune-inflammatory diseases.

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Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells

Cited by 444 publications

References 41 publications

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes

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Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells

Cited by 444 publications

References 41 publications

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes

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Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection