PD-L1 Blockade Differentially Impacts Regulatory T Cells from HIV-Infected Individuals Depending on Plasma Viremia
Peligero, Cristina (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Argilaguet, Jordi 1977- (Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut)
Güerri-Fernández, Robert (Parc de Salut Mar. Unitat de Malalties Infeccioses)
Torres, Berta (Hospital Clínic i Provincial de Barcelona)
Ligero, Carmen (Hospital Clínic i Provincial de Barcelona)
Colomer, Pilar (Parc de Salut Mar. Unitat de Malalties Infeccioses)
Plana, Montserrat (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Knobel Freud, Hernando (Parc de Salut Mar. Unitat de Malalties Infeccioses)
García, Felipe (Hospital Clínic i Provincial de Barcelona)
Meyerhans, Andreas (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Data:	2015
Resum:	Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV)-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells), which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment). However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD-L1 in vivo can be expected to influence the net gain of effector function depending on the subject's plasma viremia. HIV infection causes a progressive impairment of effector immune responses, contributing to virus persistence. The restoration of these responses is essential to achieve a drug-free control over HIV. One strategy that could restore effector immune responses is the relief of the inhibitory signal displayed by the PD-1/PD-L1 pathway on effector cells. However, the PD-1/PD-L1 pathway also plays a role in the biology of regulatory T cells, which in turn suppress effector responses. Here we show that ex vivo PD-L1 blockade on peripheral blood mononuclear cells from HIV-infected individuals differentially increases the proliferative capacity of regulatory- and effector- T cells depending on the subject's plasma viremia. Our results suggest that PD-L1 blockade will skew the effector-to-regulatory T cell ratio in favour of effector cells only in patients in whom viremia is controlled. In patients with uncontrolled viremia, PD-L1 blockade will not favour effector- T cells over regulatory- T cells, and might also boost virus reactivation. Our findings support the rationale to combine a PD-L1 blockade with antiretroviral treatment to restore effector responses in HIV-infected individuals.
Ajuts:	Ministerio de Economía y Competitividad SAF2013-46077-R Ministerio de Economía y Competitividad AP2010-3248
Nota:	Altres ajuts: FEDER/SAF2012-39075
Nota:	Altres ajuts: FEDER/FIS/PI070291
Nota:	Altres ajuts: FEDER/FIS/PI12-00969
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	PLOS pathogens, Vol. 11 (december 2015) , ISSN 1553-7374

DOI: 10.1371/journal.ppat.1005270
PMID: 26633181

20 p, 1.6 MB

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