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Role of regulatory T cells in the pathogenesis of HIV-1 infection
Retrovirology volume 6, Article number: I22 (2009)
HIV-1 infection is characterized by chronic and generalized immune activation which, in combination with the progressive depletion of CD4 T cells, profoundly perturbs antigen-specific CD8 T cell responses. The population of CD4+CD25high FoxP3+ regulatory T cells (Treg) suppresses antigen-specific T cell responses and controls inappropriate or exaggerated immune activation induced by pathogens, thereby influencing the outcome of various infections. Accumulating data pinpoint Treg as a key factor for the inefficiency of CD8-T-cell responses in viral persistence.
We have receently demonstrated that in the setting of a healthy immune system, Treg cells fine-tune the memory/effector cell balance and promote the accumulation of long-living memory cells in case of strong stimulation. These effects were at least in part mediated by a decreased expression of PD-L1, but not of programmed death 1 (PD-1), on CD8 T cells after activation (Nikolova et al, Blood. 2009).
In the setting of HIV-1 infection, we, and others, have reported an HIV-driven expansion of Treg in chronically and acutely infected patients (Weiss et al, Blood 2004; Kared et al, AIDS 2008). These cells suppress in vitro HIV-specific CD4 and CD8 effector T-cell responses. A relationship between the expansion of Treg, the level of cellular immune activation and the depletion of CD4 T cells has been shown in acutely HIV-1 infected patients.
The mechanisms by which Treg mediate their suppressive activity remain poorly understood. Treg constitutively express the ectonucleotidase CD39/ENTPD1 (Ectonucleoside triphosphate diphosphorylase-1; EC 188.8.131.52), the dominant immune system ectonucleotidase that hydrolyses extra-cellular ATP in the sites of immune activation, and generates adenosine with the help of CD73. We found a significantly increased Treg-associated expression of CD39 in HIV-1 infected patients and that the CD39-adenosinergic axis is involved in Treg-mediated inhibition of the proliferation of T cells from HIV-1 infected patients (Nikolova et al, CROI 2008, Nikolova et al, submitted). We show that effector CD8 T cells from untreated HIV-1 infected patients are more sensitive to adenosine analogues, as compared to HIV negative controls, due to a higher A2AR expression, the receptor of Adenosine. Finally, the expansion of the Treg CD39+ subset correlates with the level of immune activation and lower absolute CD4 T cell counts in HIV-1 infected patients.
Globally, these results suggest that the CD39/Adenosine pathway may be important to keep an adequate balance between activation and regulation of effector immune response in the setting of HIV-1 infection.
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Lévy, Y. Role of regulatory T cells in the pathogenesis of HIV-1 infection. Retrovirology 6, I22 (2009). https://doi.org/10.1186/1742-4690-6-S2-I22
- Treg Cell
- Immune Activation
- Ectonucleoside Triphosphate
- Healthy Immune System
- A2AR Expression