Regulatory CD4+CD25+Foxp3+ T Cells Selectively Inhibit the Spontaneous Form of Lymphopenia-Induced Proliferation of Naive T Cells

Winstead, Colleen J.; Fraser, Joanne M.; Khoruts, Alexander

doi:10.4049/jimmunol.180.11.7305

Cited by 62 publications

(67 citation statements)

References 64 publications

(65 reference statements)

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“…(76,77). Tregs play an important role in suppressing preexisting autoreactive T cells and also control the LIP of other T cell subsets to prevent the generation of autoreactive T cell clones (78,79). Our results indicate that Tregs have a more robust proliferative response to lymphopenia than Tcons, and this may be a general mechanism that suppresses the generation of autoreactive T cells under these conditions.…”

Section: Discussionmentioning

confidence: 54%

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Matsuoka¹,

Kim²,

McDonough³

et al. 2010

J. Clin. Invest.

213

211

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CD4 + CD25 + Foxp3 + Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4 + T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4 + lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4 + lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4 + lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

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Section: Discussionmentioning

confidence: 54%

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Matsuoka¹,

Kim²,

McDonough³

et al. 2010

J. Clin. Invest.

213

211

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“…Single-cell suspensions of all lymph nodes were prepared from immunized mice, and CD4 − cells were removed by negative selection and transferred to naive B6 mice (42). The reader is also referred to SI Text.…”

Section: Methodsmentioning

confidence: 99%

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Wang¹,

Dileepan²,

Briscoe³

et al. 2010

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

Self Cite

118

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Recurrent group A Streptococcus (GAS) tonsillitis and associated autoimmune diseases indicate that the immune response to this organism can be ineffective and pathological. TGF-β1 is recognized as an essential signal for generation of regulatory T cells (Tregs) and T helper (Th) 17 cells. Here, the impact of TGF-β1 induction on the Tcell response in mouse nasal-associated lymphoid tissue (NALT) following intranasal (i.n.) infections is investigated. ELISA and TGF-β1-luciferase reporter assays indicated that persistent infection of mouse NALT with GAS sets the stage for TGF-β1 and IL-6 production, signals required for promotion of a Th17 immune response. As predicted, IL-17, the Th17 signature cytokine, was induced in a TGF-β1 signaling-dependent manner in single-cell suspensions of both human tonsils and NALT. mice. These experiments link specific induction of TGF-β1 by a bacterial infection to an in vivo Th17 immune response and show that this cellular response is sufficient for protection against GAS. The association of a Th17 response with GAS infection reveals a potential mechanism for destructive autoimmune responses in humans.

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“…Because TMZ quickly increases the proportion of T Regs , and because T Regs have been shown to suppress lymphodepletioninduced homeostatic proliferation and vaccine-stimulated immunity, 34,35 we next assessed the impact of TMZ treatment on vaccine-induced immunologic responses. C57BL/6 mice were given escalating doses of TMZ before OVA immunization.…”

Section: Tmz-mediated Lymphodepletion Enhances Vaccine-induced Immunementioning

confidence: 99%

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans

Mitchell

Cui²,

Schmittling³

et al. 2011

Blood

104

101

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IntroductionThe alkylating chemotherapeutic agent temozolomide (TMZ) has been shown to prolong survival in patients with glioblastoma (GBM) and metastatic melanoma; however, patients with these diseases treated with TMZ possess a median survival of Ͻ 15 months. 1,2 Novel approaches are required to treat these devastating malignancies, and the exquisite specificity inherent to immunotherapy makes it an appealing option.Despite the potential of cancer immunotherapy, limited success has been achieved within this field due in large part to difficulties in generating appropriate numbers of high-avidity and persistent antitumor T cells. [3][4][5] A recent and profound advance in immunotherapy is the use of lymphopenia to augment antitumor immunity through adoptive cellular therapy. [6][7][8] Lymphodepletion induces homeostatic proliferation, enabling adoptively transferred activated T cells to become disproportionately overrepresented in the regenerating population and persist for months at high precursor frequencies. [9][10][11][12] Recent studies have primarily examined the lymphodepletive properties of total body irradiation (TBI), and although informative, TBI is not routinely used therapeutically and has a limited clinical context. In contrast, lymphopenia resulting from various standard-of-care chemotherapies, although generally considered an undesirable but inevitable side effect of treatment, could provide a clinically significant means to augment immunotherapy.TMZ is generally considered an immunosuppressive agent that induces lymphopenia in humans and patients receiving TMZ are routinely given prophylaxis to prevent the development of opportunistic infections. [13][14][15][16] Low-dose TMZ has been shown to enhance "cross-priming" against tumor-derived antigens in experimental mice 17 ; however, the direct effects of lymphodepletive doses of TMZ on vaccine-induced immunologic responses and regulatory T cells (T Regs ) has not been examined.Here, we report that lymphodepletive TMZ strongly augments vaccine-induced immune responses in a dose-dependent manner and that combinatorial vaccination and lymphopenia in mice bearing established B16/F10.9-OVA tumors significantly impaired malignant growth despite an increase in the frequency of CD4 ϩ CD25 ϩ Foxp3 ϩ T Regs . This TMZ-induced enhancement of immunity is dramatically augmented when combined with anti-IL-2R␣ monoclonal antibody (mAb)-mediated depletion of CD4 ϩ CD25 ϩ Foxp3 ϩ T Regs , whereas identical treatment in normal mice impaired vaccine-induced effector responses. Anti-IL-2 receptor ␣ (IL-2R␣) mAb treatment can suppress activated T cells in normal mice 18 and can suppress vaccine-induced immune responses in patients with metastatic melanoma. 19 However, to our knowledge, this is the first demonstration that the lymphopenic environment differentially impacts whether vaccination can be successfully combined with systemic antibody-mediated T Reg depletion in the treatment of established Submitted February 3, 2011; accepted July 2, 2011. Prepublished onli...

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Regulatory CD4+CD25+Foxp3+ T Cells Selectively Inhibit the Spontaneous Form of Lymphopenia-Induced Proliferation of Naive T Cells

Cited by 62 publications

References 64 publications

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Induction of TGF-β1 and TGF-β1–dependent predominant Th17 differentiation by group A streptococcal infection

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans

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