Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells

Tang, Qizhi; Henriksen, Kammi J.; Boden, Elisa K.; Tooley, Aaron J.; Ye, Jianqin; Subudhi, Sumit K.; Zheng, Xin Xiao; Strom, Terry B.; Bluestone, Jeffrey A.

doi:10.4049/jimmunol.171.7.3348

Cited by 613 publications

(568 citation statements)

References 24 publications

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“…Blocking the CD28/B7 pathway using CTLA-4 Ig molecule or anti-B7-1/2 Ab has been reported to reduce the number of T reg in both thymus and periphery [4,35]. Bluestone and collaborators [4] demonstrated that CD28 act directly on T reg to sustain their CD25 expression and therefore their response to IL-2.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…Bluestone and collaborators [4] demonstrated that CD28 act directly on T reg to sustain their CD25 expression and therefore their response to IL-2. Indeed, exogenous IL-2 administration is not able to compensate the absence of CD28 and therefore of the CD25 expression [4]. We did not observed down regulation of CD25 expression neither on T reg from CD40KO mice nor on wt T reg transferred in CD40KO mice or on T reg from wt mice treated with CD40L blocking Ab, thus suggesting that CD40 controls peripheral pool using a different mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Costimulatory molecules have also a role. Mice KO for CD28 or its ligands B7-1 and B7-2 have less T reg than wt counterpart [4]. CD28 provides a costimulatory signal necessary for the thymic development and their maintenance in the periphery by promoting self-renewal [4,5].…”

Section: Introductionmentioning

confidence: 99%

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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CD4 + CD25 + regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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“…Regulatory T cells are indeed dependent on CD28 for their development and survival, thus the use of CTLA-4Ig can induce a drastic reduction of this cell population and exacerbate the autoimmune process. 109,110 Despite the intricacies of co-stimulatory modulation, CTLA-4Ig has been developed and tested in patients with autoimmune diseases.…”

Section: Co-stimulatory Blockade Treatments In Human Autoimmune Diseasesmentioning

confidence: 99%

Modulating Co-Stimulation

Viglietta

Khoury

2007

Neurotherapeutics

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Summary:The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4ϩ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing autoantigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.

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Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis

et al. 2021

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IMPORTANCEPsoriasis relapse may involve compensatory T-cell activation pathways in the presence of CD28-CD80/CD86 blockade with abatacept.OBJECTIVE To determine whether costimulatory signaling blockade with abatacept prevents psoriasis relapse after ustekinumab withdrawal.DESIGN, SETTING, AND PARTICIPANTS Psoriasis Treatment with Abatacept and Ustekinumab: a Study of Efficacy (PAUSE), a parallel-design, double-blind, placebo-controlled randomized clinical trial, was conducted at 10 sites in the US and Canada. Participant enrollment opened on March 19, 2014, and concluded on April 11, 2016. Participants were adults with moderate to severe plaque psoriasis and received ustekinumab in a lead-in phase. Those who responded to ustekinumab at week 12 were randomized 1:1 to either the continued with ustekinumab group (ustekinumab group) or the switched to abatacept group (abatacept group). Treatment was discontinued at week 39, and participants were followed up for psoriasis relapse until week 88. Statistical analyses were performed in the intention-to-treat (ITT) and safety samples from May 3, 2018, to July 6, 2021.INTERVENTIONS Participants received subcutaneous ustekinumab at weeks 0 and 4 (45 mg per dose for those Յ100 kg; 90 mg per dose for those >100 kg). Participants randomized to the abatacept group at week 12 received subcutaneous abatacept, 125 mg weekly, from weeks 12 to 39 and ustekinumab placebo at weeks 16 and 28. Participants randomized to the ustekinumab group received ustekinumab at weeks 16 and 28 and abatacept placebo weekly from weeks 12 to 39. MAIN OUTCOMES AND MEASURESThe primary end point was the proportion of participants with psoriasis relapse (loss of Ն50% of the initial Psoriasis Area and Severity Index improvement) between weeks 12 and 88. Secondary end points included time to psoriasis relapse, proportion of participants with psoriasis relapse between weeks 12 and 40, and adverse events. The psoriasis transcriptome and serum cytokines were evaluated.RESULTS A total of 108 participants (mean [SD] age, 46.1 [12.1] years; 73 [67.6%] men) were treated with open-label ustekinumab; 91 were randomized to blinded treatment. Similar proportions of participants in the abatacept group and the ustekinumab group relapsed between weeks 12 and 88 (41 of 45 [91.1%] vs 40 of 46 [87.0%]; P = .41). Median time to relapse from the last dose of ustekinumab was similar between groups as well: 36 weeks (95% CI, 36-48 weeks) in the abatacept group vs 32 weeks (95% CI, 28-40 weeks) in the ustekinumab group. Similar numbers and rates of adverse events occurred. Abatacept did not maintain suppression of the pathogenic IL-23-mediated psoriasis molecular signature in lesions after ustekinumab withdrawal, and serum IL-19 levels increased.CONCLUSIONS AND RELEVANCE This parallel-design, double-blind randomized clinical trial found that abatacept did not prevent psoriasis relapse that occurred after ustekinumab withdrawal because it did not completely block the pathogenic psoriasis molecular pathways that led to relapse.

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Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells

Cited by 613 publications

References 24 publications

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

Modulating Co-Stimulation

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis

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Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells

Cited by 613 publications

References 24 publications

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

Modulating Co-Stimulation

Effect of Costimulatory Blockade With Abatacept After Ustekinumab Withdrawal in Patients With Moderate to Severe Plaque Psoriasis

Contact Info

Product

Resources

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2