3ITD

Impact of IL-7 and IFNa on nTreg development

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 Obiettivo del progetto (Objective)

'In developed countries, most HIV-infected patients are under highly active antiretroviral therapy (HAART). However, despite controlled viral replication, the immune reconstitution often remains incomplete, probably due to a poor reconstitution of thymic production. Apart its role in educating a diverse repertoire of conventional T-cells, the thymus also produces natural regulatory T-cells (nTreg), which contributes to the regulation of immune responses. Various cytokines are presently proposed as immunotherapy susceptible to help reconstituting circulating T-cell pool. Among these, Interleukin-7 is certainly the more promising as it directly affects thymic function, allowing T-cell neo-production and thus the enlargement of circulating T-cell repertoire diversity. The 3ITD project aims to a) analyze the physiology of nTreg production by the thymus; b) precisely evaluate the impact of acute SIV infection on nTreg production and identify the cytokines involved in early thymic defects; c) realize a pre-clinical study using recombinant IL-7 as a potential therapeutic to reconstitute nTreg subset in chronically HIV-infected patients and in HIV/HCV co-infected patients presenting with IFNα therapy-induced lymphopenia. The 3ITD project will be developed in 3 stages: a) definition of the phenotype of nTregs recently emigrated from the thymus; b) estimation of the impact of acute SIV infection and IFNα therapy; c) evaluation of the relevance of IL-7 treatment. The 3ITD project will provide a better understanding of the physiology of nTregs maturation by the thymus and of the modifications induced by HIV infection. Moreover, the 3ITD project will provide pre-clinical rationale for the use of IL-7 as a therapeutic compound in the treatment of virally- or pharmaceutically-induced nTreg deficiencies. It will impact the researcher’s growth and contribute to European excellence and knowledge transfer. Thus it is relevant to People specific, Capacity and Cooperation EC Program.'

Introduzione (Teaser)

HIV patients are given highly active antiretroviral therapy (HAART) to control virus replication but the mechanisms by which HIV affects immune regulation remains a mystery. A European study concentrated on the 'natural' subset of regulatory T cells to elucidate how HIV impairs T cell development and function.

Descrizione progetto (Article)

Extensive research has shown that HIV impairs regulatory T cells by infecting the thymus and affecting its function. Of particular relevance to HIV infection are the natural regulatory T cells (nTregs) that get selected by high-avidity interactions in the thymus to control immune responses. Lack of specific markers to distinguish natural from inducible regulatory T cells has hampered the extensive investigation of nTregs.

The EU-funded 'Impact of IL-7 and IFNa on nTreg development' (3ITD) project investigated the phenotype and function of nTregs that emigrate from the thymus. The mechanisms by which these cells are implicated in immune responses were also looked into.

Studies on T cells revealed that the fraction of nTregs that emigrated from the thymus lacked expression of CD127 but was positive for CD25. CD25 is a protein present on interleukin-2 (IL-2) receptor (usually present on Tcell activation). CD127 is a protein found on the IL-7 receptor, critical for immune cell development. CD25 cells were encountered at reduced levels in the peripheral blood of HIV patients when compared to controls. Similar findings have been reported in Simian immunodeficiency virus (SIV)-infected animals as well as in autoimmune patients.

Study findings suggest that the acquisition of CD25 may be a result of the interaction between immature T cells and the thymus. Additionally, the low CD25 expression in the regulatory T cells of HIV patients could be a result of an impaired activation in the thymus. Using in vitro functional assays, scientists further proved the impaired activation in natural regulatory T cells lacking in CD25.

Apart from providing important knowledge on the T cell maturation process in the thymus, 3ITD study results have clinical implications. Natural regulatory T cells could be utilised in clinical practice to provide immune-based therapies that can reconstitute a functional immune system after HIV infection.