Control of homeostatic proliferation by regulatory T cells

Shen, Shiqian; Ding, Yi; Tadokoro, Carlos E.; Olivares–Villagómez, Danyvid; Camps-Ramirez, Marlin; Lafaille, Maria A. Curotto de; Lafaille, Juan J.

doi:10.1172/jci25463

Cited by 85 publications

(78 citation statements)

References 86 publications

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“…Nonetheless, we tested their suppressive capacity by an indirect method, where we performed skin transplantations from these groups (Control, NI bite, and INF bite) to nude animals. In these immune-compromised nude animals, CD4 T cells expand by homeostatic proliferation, which can be suppressed by Tregs [16]. In our experiments, we observed that homeostatic proliferation was lower in recipients of INF bitten skins as compared with those of NI bitten skins (Fig.…”

Section: Reduced Homeostatic Proliferation Of Skin-migrated Cd4 T Cellsmentioning

confidence: 48%

“…Homeostatic proliferation is controlled by Tregs [16]. In order to indirectly measure the suppressive capacity of skin-migrated Tregs, we performed a homeostatic proliferation assay, measuring the amount of CD4 T cells that could be found in spleen, mesenteric, and inguinal LNs of immune-compromised animals, 14 days after skin transplantations.…”

Section: Homeostatic Proliferation To In Vivo Tests Treg Functionmentioning

confidence: 99%

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Early skin immunological disturbance after Plasmodium-infected mosquito bites

Silva

Caetano

Monteiro

et al. 2012

Cellular Immunology

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a b s t r a c tAlthough the role of regulatory T cells (Tregs) during malaria infection has been studied extensively, such studies have focused exclusively on the role of Treg during the blood stage of infection; little is known about the detailed mechanisms of Tregs and sporozoite deposition in the dermis by mosquito bites. In this paper we show that sporozoites introduced into the skin by mosquito bites increase the mobility of skin Tregs and dendritic cells (DCs). We also show differences in MHC class II and/or CD86 expression on skin-resident dendritic cell subtypes and macrophages. From the observed decrease of the number of APCs into draining lymph nodes, suppression of CD28 expression in conventional CD4 T cells, and a low homeostatic proliferation of skin-migrated CD4 T found in nude mice indicate that Tregs may play a fundamental role during the initial phase of malaria parasite inoculation into the mammalian host.

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Section: Reduced Homeostatic Proliferation Of Skin-migrated Cd4 T Cellsmentioning

confidence: 48%

Section: Homeostatic Proliferation To In Vivo Tests Treg Functionmentioning

confidence: 99%

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Silva

Caetano

Monteiro

et al. 2012

Cellular Immunology

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“…A recent report (61) suggests that regulatory T cells can control homeostatic proliferation. The notion of combining anti-T cell treatment to deplete the bulk of alloreactive T cells with regulatory T cells to control the remaining T cell population has already been suggested and experimentally demonstrated to be effective as an adjunct to tolerance induction by Turka and colleagues (51).…”

Section: Discussionmentioning

confidence: 99%

Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection

Moxham¹,

Karegli²,

Phillips³

et al. 2008

The Journal of Immunology

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Homeostatic proliferation is a normal physiological process triggered by lymphopenia to maintain a constant level of T cells. It becomes the predominant source of new T cells in adulthood after thymus regression. T cells that have undergone homeostatic proliferation acquire the memory phenotype, cause autoimmune disease, and are resistant to tolerance induction protocols. Transplantation is a rare example in which lymphopenia is deliberately induced for its immunosuppressive effect. However, it is not known whether the homeostatic proliferation that follows will have the opposite effect and accelerate rejection. We show that T cells that have undergone homeostatic proliferation acquire a memory phenotype, spontaneously skews toward the Th1 phenotype, even in the absence of antigenic stimulus. Interestingly, in contrast, the percentage of Foxp3+ regulatory T cells increased by 28-fold following homeostatic proliferation. Using a mouse life-sustaining kidney transplant model, we showed that T cells that have gone through homeostatic proliferation in lymphopenic hosts transformed chronic rejection to acute rejection of a single MHC class II-mismatched kidney allograft. T cells that have undergone homeostatic proliferation consistently cause reliable rejection even when bona fide memory T cells cannot. These functional changes are long-lasting and not restricted to the acute phase of homeostatic proliferation. Our findings have important implications for tolerance induction or graft-prolonging protocols involving leukocyte depletion such as irradiation bone marrow chimera, T cell-depleting Abs, and lymphopenia induced by infections such as CMV and HIV.

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“…It has been hypothesized that Tregs inhibit the development of autoreactive T cells (10). Thus, T cells that express CTLA-4 play a crucial role in immune homeostasis.…”

Section: Induction Of the Ctla-4 Gene In Human Lymphocytes Is Dependementioning

confidence: 99%

Induction of the CTLA-4 Gene in Human Lymphocytes Is Dependent on NFAT Binding the Proximal Promoter

Gibson

Hedgcock

Aufiero

et al. 2007

The Journal of Immunology

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CTLA-4 is a member of the costimulatory family, has homology to CD28, and binds the B7 family of ligands. Unlike CD28, CTLA-4 ligation transmits a negative signal in T cells. CTLA-4 expression, while inducible in most T cells, is expressed constitutively on T cells with a regulatory phenotype. The mechanism controlling CTLA-4 expression in human T cells is poorly characterized, thus we sought to better understand the mechanism of activation of the CTLA-4 gene. By cloning the 5′ upstream promoter and creating promoter-deletion reporter constructs, we show that the proximal promoter is critical for activating the CTLA-4 gene. Within this region, we identify a NFAT consensus sequence that binds NFAT with high affinity that differs from other NFAT sequences and does not recruit AP-1. Analysis of the chromatin proteins in the native CTLA-4 gene shows that this promoter region becomes associated with acetylated histones by chromatin immunoprecipitation assays. In addition, NFAT1 binds to the promoter of the CTLA-4 gene after stimulation by chromatin immunoprecipitation. The functional requirement of the NFAT site for CTLA-4 transcription was demonstrated by mutations in the NFAT site that abolished the activity of the promoter. Furthermore, inhibitors of NFAT suppressed CTLA-4 gene expression, indicating that NFAT plays a critical role in regulating the induction of the CTLA-4 gene in lymphocytes. The identification of NFAT as a critical regulator of the CTLA-4 gene suggests that targeting NFAT function may lead to novel approaches to modulate the CTLA-4 gene to control the immune response.

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Control of homeostatic proliferation by regulatory T cells

Cited by 85 publications

References 86 publications

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Early skin immunological disturbance after Plasmodium-infected mosquito bites

Homeostatic Proliferation of Lymphocytes Results in Augmented Memory-Like Function and Accelerated Allograft Rejection

Induction of the CTLA-4 Gene in Human Lymphocytes Is Dependent on NFAT Binding the Proximal Promoter

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