RESUMO
Follicular CD4+ T cells are the main HIV reservoirs due to, among other factors, the low frequency of CD8+ T cells in lymphoid follicles. Follicular CXCR5+ CD8+ T cells are associated with HIV control, but their differentiation conditions are yet undefined. In this study, we explored the in vitro effect of transforming growth factor (TGF)-ß1, interleukin (IL)-12, and IL-23 on the induction of CXCR5, the follicle homing receptor, in human circulating CD8+ T cells from seronegative, and treated HIV-infected individuals. The combination of TGF-ß1 plus IL-23 induced the highest expression of CXCR5 in purified CD8+ T cells. These CXCR5+ CD8+ T cells also expressed a transcriptional and phenotypic profile similar to that of follicular CD4+ T cells, such as the upregulation of BCL6, inducible costimulator and CD40L, and downregulation of PRDM1. These cells responded in vitro to CXCL13 and had low expression of CCR7. In addition, after polyclonal stimulation, they produced IL-21, interferon-γ, and de novo perforin. However, in comparison with seronegative individuals, CD8+ T cells from HIV-infected patients had a lower response to TGF-ß1/IL-23, a defect that was restored with the blockade of the programmed cell death 1 inhibitory receptor. Thus, TGF-ß1 plus IL-23 induce follicular-like CXCR5+ CD8+ T cells in seronegative individuals, but in HIV-infected patients there is a limited response which could impair the generation of this cell population.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Interleucina-23/farmacologia , Receptores CXCR5/imunologia , Fator de Crescimento Transformador beta1/farmacologia , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Quimiocina CXCL13/farmacologia , Soronegatividade para HIV/imunologia , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma/efeitos dos fármacos , Transcriptoma/imunologia , Adulto JovemRESUMO
Immune activation is the hallmark of HIV infection, even in patients with highly active anti-retroviral therapy (HAART)-induced viral suppression. A major cause of immune activation during HIV infection is the intestinal microbial translocation as a consequence, among other factors, of the decrease and/or dysfunction of interleukin (IL)-17-producing T-cells, due to their role promoting the integrity of the intestinal barrier. A population of IL-17-producing CD8+ T-cells (Tc17 cells), characterized by the expression of CD161, has been described, but its relation with the persistent immune activation in non-viremic people living with HIV (PLWH) on HAART is unclear. By flow cytometry, we characterized the activation phenotype (evaluated by the expression of HLA-DR and CD38) of circulating CD161-expressing CD8+ T-cells; in addition, we explored the functionality of polyclonally-stimulated Tc17 cells in PLWH under HAART-induced viral suppression, and in healthy individuals. Finally, we determined the association of Tc17 cells with the expression of cellular and soluble activation markers. Circulating CD161-expressing CD8+ T-cells were decreased in PLWH compared with healthy individuals, despite their similar basal activation state. After polyclonal stimulation, IL-17 production was higher in CD8+ T-cells co-expressing HLA-DR and CD38 in healthy individuals. In contrast, although PLWH had a higher frequency of HLA-DR+ CD38+ CD8+ T-cells after stimulation, they had a lower production of IL-17. Interferon (IFN)-γ-producing CD8+ T-cells (Tc1 cells) were increased in PLWH. The low Tc17 cells response was associated with a high expression of CD38 and programmed death 1 protein, high levels of soluble CD14 and the treatment duration. Finally, to explore potential immunomodulatory strategies, the in vitro effect of the anti-inflammatory agent sulfasalazine was assessed on Tc17 cells. Interestingly, a decreased inflammatory environment, death of activated CD8+ T-cells, and an increased frequency of Tc17 cells were observed with sulfasalazine treatment. Thus, our findings suggest that activated CD8+ T-cells have a marked capacity to produce IL-17 in healthy individuals, but not in PLWH, despite HAART. This dysfunction of Tc17 cells is associated with the persistent immune activation observed in these patients, and can be partially restored by anti-inflammatory agents.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Adulto , Anti-Inflamatórios/farmacologia , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Cultivadas , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Imunofenotipagem , Interleucina-17/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Sulfassalazina/farmacologia , Carga Viral , Latência Viral , Adulto JovemRESUMO
HIV infection induces alterations in almost all immune cell populations, mainly in CD4+ T cells, leading to the development of opportunistic infections. The gut-associated lymphoid tissue (GALT) constitutes the most important site for viral replication, because the main target cells, memory T-cells, reside in this tissue. It is currently known that alterations in GALT are critical during the course of the infection, as HIV-1 induces loss of tissue integrity and promotes translocation of microbial products from the intestinal lumen to the systemic circulation, leading to a persistent immune activation state and immune exhaustion. Although antiretroviral treatment decreases viral load and substantially improves the prognosis of the infection, the alterations in GALT remains, having a great impact on the ability to establish effective immune responses. This emphasizes the importance of developing new therapeutic alternatives that may promote structural and functional integrity of this tissue. In this regard, therapy with probiotics/prebiotics has beneficial effects in GALT, mainly in syndromes characterized by intestinal dysbiosis, including the HIV-1 infection. In these patients, the consumption of probiotics/prebiotics decreased microbial products in plasma and CD4+ T cell activation, increased CD4+ T cell frequency, in particular Th17, and improved the intestinal flora. In this review, the most important findings on the potential impact of the probiotics/prebiotics therapy are discussed.
Assuntos
Trato Gastrointestinal/virologia , Infecções por HIV/dietoterapia , Tecido Linfoide/virologia , Prebióticos/administração & dosagem , Probióticos/administração & dosagem , Linfócitos T CD4-Positivos , Trato Gastrointestinal/metabolismo , Humanos , Tecido Linfoide/metabolismo , Carga ViralRESUMO
HIV infection induces alterations in almost all immune cell populations, mainly in CD4+ T cells, leading to the development of opportunistic infections. The gut-associated lymphoid tissue (GALT) constitutes the most important site for viral replication, because the main target cells, memory T-cells, reside in this tissue. It is currently known that alterations in GALT are critical during the course of the infection, as HIV-1 induces loss of tissue integrity and promotes translocation of microbial products from the intestinal lumen to the systemic circulation, leading to a persistent immune activation state and immune exhaustion. Although antiretroviral treatment decreases viral load and substantially improves the prognosis of the infection, the alterations in GALT remains, having a great impact on the ability to establish effective immune responses. This emphasizes the importance of developing new therapeutic alternatives that may promote structural and functional integrity of this tissue. In this regard, therapy with probiotics/prebiotics has beneficial effects in GALT, mainly in syndromes characterized by intestinal dysbiosis, including the HIV-1 infection. In these patients, the consumption of probiotics/prebiotics decreased microbial products in plasma and CD4+ T cell activation, increased CD4+ T cell frequency, in particular Th17, and improved the intestinal flora. In this review, the most important findings on the potential impact of the probiotics/prebiotics therapy are discussed.