Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells

Wang, Rui; Kozhaya, Lina; Mercer, Frances; Khaitan, Alka; Fujii, Hodaka; Unutmaz, Derya

doi:10.1073/pnas.0901965106

Cited by 225 publications

(266 citation statements)

References 25 publications

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“…As expected, many of the genes differentially expressed at week 0 (FOXP3, CTLA4, IL10, FAS, LRRC32 (GARP), CCR8, and IL1R1) have been associated with phenotype or function of Treg (23)(24)(25)(26) (Fig. 4).…”

Section: Cd4 + Cd25 + Il-2-expanded T Cells Exhibit Functional Characmentioning

confidence: 87%

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Weiss

Letimier

Carrière

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 infection is characterized by a progressive decline in CD4 + T cells leading to a state of profound immunodeficiency. IL-2 therapy has been shown to improve CD4 + counts beyond that observed with antiretroviral therapy. Recent phase III trials revealed that despite a sustained increase in CD4 + counts, IL-2-treated patients did not experience a better clinical outcome [Abrams D, et al. (2009) N Engl J Med 361(16):1548-1559. To explain these disappointing results, we have studied phenotypic, functional, and molecular characteristics of CD4 + T cell populations in IL-2-treated patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4 + CD25 + T cell populations (CD4 + CD25 lo CD127 lo FOXP3 + and CD4 + CD25 hi CD127 lo FOXP3 hi ) that shared phenotypic markers of Treg but could be distinguished by the levels of CD25 and FOXP3 expression. IL-2-expanded CD4 + CD25 + T cells suppressed proliferation of effector cells in vitro and had gene expression profiles similar to those of natural regulatory CD4 + CD25 hi FOXP3 + T cells (Treg) from healthy donors, an immunosuppressive T cell subset critically important for the maintenance of self-tolerance. We propose that the sustained increase of the peripheral Treg pool in IL-2-treated HIV patients may account for the unexpected clinical observation that patients with the greatest expansion of CD4 + T cells had a higher relative risk of clinical progression to AIDS. molecular profiling | immune-based therapy H IV infection is mainly associated with a progressive decrease in the number of CD4 + T lymphocytes and defective CD4-and CD8-specific T cell responses against HIV and other pathogens. Quantitative and qualitative CD4 T cell reconstitution following introduction of antiretroviral therapy (ART) in HIVinfected patients is often incomplete, leading one to evaluate the impact of immune-based therapy in combination with ART. In the past 20 years, a large set of clinical trials demonstrated that intermittent interleukin (IL)-2 therapy increased the CD4 T cell pool in HIV-infected patients and induced, in a large majority of patients, significant and sustained increases in CD4 T cell count beyond that seen in patients treated with antiviral drugs alone. In particular, recombinant IL-2 therapy raised naive and central memory CD4 + cells expressing CD25, the α-chain of the IL-2 receptor, more than antiretroviral drugs alone (1-6). This population accounted for up to 70% of the total CD4 + T cell pool of IL-2-treated patients and persisted for a long time.The clinical impact of IL-2 was evaluated in two long-run large phase III trials (SILCAAT and ESPRIT) involving almost 6,000 chronically HIV-1-infected patients. Results recently reported showed that, despite a sustained increase in CD4 + T cell counts, over a median follow-up of 7-8 years, IL-2-treated patients did not experience a better clinical outcome (7). These disappointing results have remained unexplained so far.In mice, IL-2 has been shown to be essential for the...

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Section: Cd4 + Cd25 + Il-2-expanded T Cells Exhibit Functional Characmentioning

confidence: 87%

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Weiss

Letimier

Carrière

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…We observed a relative reduction of both T cell subsets in the spleens and in the mLNs of CAC mice. Conversely, in tumorbearing colons, the proportion of CD4 þ T cells was signif- (20)(21)(22). In the spleens and the mLNs, as many as 10% of the CD4 þ T cells expressed GARP, CD103, and CTLA-4, independent of whether the cells were isolated from healthy or diseased mice.…”

Section: Accumulation Of Treg In Cacmentioning

confidence: 98%

Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer

et al. 2014

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“…Moreover, the control of autoreactive T cells by Treg cells in vivo may also occur through TGF-b signaling. Activated human and murine Treg cells express the glycoprotein A repetitions predominant (GARP) protein, which associates with the latent form of TGF-b, resulting in cell-surface expression of TGF-b on Treg cells (Stockis et al 2009;Tran et al 2009;Wang et al 2009;Edwards et al 2013). Indeed, active TGFb can be generated from the membrane-bound complex of GARP and latent TGF-b .…”

Section: Tolerancementioning

confidence: 99%

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Sanjabi

2017

Cold Spring Harb Perspect Biol

452

306

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Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses. After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions. Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naïve T-cell pool. TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral ( p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges. Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes. Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self-and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.

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Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells

Cited by 225 publications

References 25 publications

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

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Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells

Cited by 225 publications

References 25 publications

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

In vivo expansion of naive and activated CD4 + CD25 + FOXP3 + regulatory T cell populations in interleukin-2–treated HIV patients

Transient Ablation of Regulatory T cells Improves Antitumor Immunity in Colitis-Associated Colon Cancer

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

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Product

Resources

About

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients

In vivo expansion of naive and activated CD4 ⁺ CD25 ⁺ FOXP3 ⁺ regulatory T cell populations in interleukin-2–treated HIV patients