new-tools-to-expand-regulatory-t-cells-from-hiv-1-infected-individuals

New Tools to Expand Regulatory T Cells from HIV-1-infected Individuals

CD4+ Regulatory T cells (Tregs) are potent immune modulators and serve an important function in human immune homeostasis. Depletion of Tregs has led to ...

Although clinical trials using anti-CD40L mAb have been halted, blockade of CD40-CD40L interactions has given promising results in rodent and nonhuman primate models. Recently, new insights into the consequences of blocking CD40-CD40L interactions have led to the possibility of overcoming the thromboembolic complications previously associated with this strategy and may pave the way for successful tolerance induction. This mini review will address the issues relating to CD40-CD40L blockade in allotransplantation.

Promises and obstacles for the blockade of CD40-CD40L interactions in allotransplantation.

Despite accumulating evidence for the importance of allospecific CD8(+) regulatory T cells (Tregs) in tolerant rodents and free immunosuppression transplant recipients, mechanisms underlying CD8(+) Treg-mediated tolerance remain unclear. By using a model of transplantation tolerance mediated by CD8(+) Tregs following CD40Ig treatment in rats, in this study, we show that the accumulation of tolerogenic CD8(+) Tregs and plasmacytoid dendritic cells (pDCs) in allograft and spleen but not lymph nodes was associated with tolerance induction in vascularized allograft recipients. pDCs preferentially induced tolerogenic CD8(+) Tregs to suppress CD4(+) effector cells responses to first-donor Ags in vitro. When tolerogenic CD8(+) Tregs were not in contact with CD4(+) effector cells, suppression was mediated by IDO. Contact with CD4(+) effector cells resulted in alternative suppressive mechanisms implicating IFN-gamma and fibroleukin-2. In vivo, both IDO and IFN-gamma were involved in tolerance induction, suggesting that contact with CD4(+) effector cells is crucial to modulate CD8(+) Tregs function in vivo. In conclusion, CD8(+) Tregs and pDCs interactions were necessary for suppression of CD4(+) T cells and involved different mechanisms modulated by the presence of cell contact between CD8(+) Tregs, pDCs, and CD4(+) effector cells.

Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance.

Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1-specific T cell responses.

Regulatory T cells (Tregs) are potent immune modulators, but their role in human immunodeficiency virus type 1 (HIV-1) pathogenesis remains poorly understood. We performed a detailed analysis of the frequency and function of Tregs in a large cohort of HIV-1-infected individuals and HIV-1 negative controls. While HIV "elite controllers" and uninfected individuals had similar Treg numbers and frequencies, the absolute numbers of Tregs declined in blood and gut-associated lymphoid tissue in patients with chronic progressive HIV-1 infection. Despite quantitative changes in Tregs, HIV-1 infection was not associated with an impairment of ex vivo suppressive function of flow-sorted Tregs in both HIV controllers and untreated chronic progressors.

Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue.

T cell dysfunction in the presence of ongoing antigen exposure is a cardinal feature of chronic viral infections with persistent high viremia, including HIV-1. Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-Î³) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-Î³ secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14(+) monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-Î±), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.

CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.

T cell immunoglobulin and mucin domainâ€“containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9â€“mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigenâ€“specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-Î³ (IFN-Î³)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1â€“infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3â€“dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.

Bat3 promotes T cell responses and autoimmunity by repressing Tim-3â€“mediated cell death and exhaustion.

Regulatory T cells (Tregs) are potent immune modulators, but their precise role in HIV pathogenesis remains incompletely understood. Most studies to date have focused on frequencies or phenotypes of 'bulk' Treg populations. However, although antigen-specific Tregs have been reported in other diseases, HIV-1 epitope-specific Tregs have not been described to date. We here report the first identification of functional HIV-1-Gag-specific regulatory T cells using human leukocyte antigen class II tetramer staining in HIV-1-infected individuals.

Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers.

Blockade of costimulation signaling required for immune response, such as CD40/CD40L and CD28/B7, is a reasonable strategy to prevent rejection and in defined combinations may allow donor specific tolerance. Indeed, in rodents, costimulation blockade with CD28/B7 antagonists or with CD40Ig was able to induce regulatory T cells and transplant tolerance whereas in primates, anti-CD40 antibodies, anti-CD40L antibodies or CTLA4Ig, used as monotherapy, significantly delayed graft rejection.

Article	Year
Promises and obstacles for the blockade of CD40-CD40L interactions in allotransplantation. Transplantation\| PubMed ID: 18622269	2008
Mechanism and localization of CD8 regulatory T cells in a heart transplant model of tolerance. Journal of immunology (Baltimore, Md. : 1950)\| PubMed ID: 20543104	2010
Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1-specific T cell responses. AIDS research and human retroviruses\| PubMed ID: 22214208	2012
Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue. The Journal of infectious diseases\| PubMed ID: 22427677	2012
CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes. Journal of virology\| PubMed ID: 22496237	2012
Bat3 promotes T cell responses and autoimmunity by repressing Tim-3â€“mediated cell death and exhaustion. Nature medicine\| PubMed ID: 22863785	2012
Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers. AIDS (London, England)\| PubMed ID: 22874519	2012
Gene transfer of human CD40Ig does not prevent rejection in a non-human primate kidney allotransplantation model. Transplant immunology\| PubMed ID: 23098770	2012

Mathieu Angin

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