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Background There are contradictory reports on the effects of obstructive sleep apnea (OSA) on the immune system. In order to clarify the effect of OSA on the different components of the immune system, we studied the association of OSA with changes in cytokine and chemokine levels, proliferative patterns of CD4 and CD8 T lymphocytes as well as NK cells ex vivo and neutrophil functions. Methods We investigated the association of OSA with potential alterations in 14 Th1/Th2 and inflammatory cytokines and chemokines, CD4 and CD8 T cells, NK cells, and the NADPH oxidase activation and phagocytic functions in neutrophils. Results Our results suggest that the increase in CD4 T cell frequency in OSA is associated with an increased expression of the nuclear protein Ki67 ( p < 0.05; power > 0.8), and is correlated with the levels of IL-1β ( p < 0.05; power > 0.8). The levels of IL-1β as well as IL-6 showed a potential increase, while the levels of IFN-γ ( p < 0.05; power > 0.8) and the ratio IFN-γ/IL-4 in the blood were possibly decreased in OSA. Additionally, we observed a potential increase in the expression of Ki67 in CD8 hi and CD8 lo NK cells ( p < 0.05; power > 0.8). Our results also suggest that neutrophils have a decreased capacity to phagocytose bacteria and activate NADPH oxidase in OSA patients ( p < 0.05; power > 0.8). Conclusion OSA may be associated with inflammatory and pro-Th2 immune responses, an increased proliferative potential of NK and CD4 T cells and a decreased capacity of neutrophils to phagocytose bacteria and produce ROS. [ABSTRACT FROM AUTHOR]

Background: The failure to establish potent anti-HBV T cell responses suggests the absence of an effective innate immune activation. Kupffer cells and liver-infiltrating monocytes/macrophages have an essential role in establishing anti-HBV responses. These cells express the costimulatory molecules CD80 and CD86. CD80 expression on antigen-presenting cells (APCs) induces Th1 cell differentiation, whereas CD86 expression drives the differentiation towards a Th2 profile. The relative expression of CD80, CD86 and PD-L1 on APCs, regulates T cell activation. Few studies investigated CD80 and CD86 expression on KCs and infiltrating monocytes/macrophages in HBV-infected liver and knowledge about the expression of PD-L1 on these cells is controversial. The expression of these molecules together in CD68+ cells has not been explored in HBV-infected livers. Methods: Double staining immunohistochemistry was applied to liver biopsies of HBV-infected and control donors to explore CD80, CD86 and PD-L1 expression in the lobular and portal areas. Results: Chronic HBV infection was associated with increased CD68+CD86+ cell count and percentage in the lobular areas, and no changes in the count and percentage of CD68+CD80+ and CD68+PD-L1+ cells, compared to the control group. While CD68+CD80+ cell count in portal areas correlated with the fibrosis score, CD68+CD80+ cell percentage in lobular areas correlated with the inflammation grade. Conclusion: The upregulation of CD86 but not CD80 and PD-L1 on CD68+ cells in HBV-infected livers, suggests that these cells do not support the induction of potent Th1. Moreover, the expression of CD80 on CD68+ cells correlates with liver inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Aim: The lack of potent innate immune responses during HCV infection might lead to a delay in initiating adaptive immune responses. Kupffer cells (KCs) and liver-infiltrating monocytes/macrophages (CD68+ cells) are essential to establish effective anti-HCV responses. They express co-stimulatory molecules, CD80 and CD86. CD86 upregulation induces activator responses that are then potentially regulated by CD80. The relative levels of expression of CD80, CD86 and the inhibitory molecule, PD-L1, on CD68+ cells modulate T cell activation. A few studies have explored CD80 and PD-L1 expression on KCs and infiltrating monocytes/macrophages in HCV-infected livers, and none investigated CD86 expression in these cells. These studies have identified these cells based on morphology only. We investigated the stimulatory/inhibitory profile of CD68+ cells in HCV-infected livers based on the balance of CD80, CD86 and PD-L1 expression. Methods: CD80, CD86 and PD-L1 expression by CD68+ cells in the lobular and portal areas of the liver of chronic HCV-infected (n = 16) and control (n = 14) individuals was investigated using double staining immunohistochemistry. Results: The count of CD68+ KCs in the lobular areas of the HCV-infected livers was lower than that in the control (p = 0.041). The frequencies of CD68+CD80+ cells and CD68+PD-L1+ cells in both lobular and total areas of the liver were higher in HCV-infected patients compared with those in the control group (p = 0.001, 0.031 and 0.007 respectively). Moreover, in the lobular areas of the HCV-infected livers, the frequency of CD68+CD80+ cells was higher than that of CD68+CD86+ and CD68+PD-L1+ cells. In addition, the frequencies of CD68+CD80+ and CD68+CD86+ cells were higher in the lobular areas than the portal areas. Conclusions: Our results show that CD68+ cells have an inhibitory profile in the HCV-infected livers. This might help explain the delayed T cell response and viral persistence during HCV infection. [ABSTRACT FROM AUTHOR]

Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1. [ABSTRACT FROM AUTHOR]

The persistence of central memory CD4+ T cells (TCM cells) is a major correlate of immunological protection in HIV/AIDS, as the rate of TCM cell decline predicts HIV disease progression. In this study, we show that TCM cells and effector memory CD4+ T cells (TEM cells) from HIV+ elite controller (EC) subjects are less susceptible to Fas-mediated apoptosis and persist longer after multiple rounds of T cell receptor triggering when compared to TCM and TEM cells from aviremic successfully treated (ST) subjects or from HIV− donors. We show that persistence of TCM cells from EC subjects is a direct consequence of inactivation of the FOXO3a pathway. Silencing the transcriptionally active form of FOXO3a by small interfering RNA or by introducing a FOXO3a dominant-negative form (FOXO3a Nt) extended the long-term survival of TCM cells from ST subjects to a length of time similar to that of TCM cells from EC subjects. The crucial role of FOXO3a in the survival of memory cells will help shed light on the underlying immunological mechanisms that control viral replication in EC subjects. [ABSTRACT FROM AUTHOR]

Long-term maintenance of memory T cell response is the hallmark of immune protection and hence the holy grail of most vaccine development studies. Persistent memory cells, developed after either viral infection or vaccination, ensure the generation of an antiviral response upon reexposure to the pathogen. During acute viral infections, as in the case of measles and influenza viruses, strong T cell effector functions, which eradicate the virus and protect patients against reexposure, are achieved by the generation of persistent protective memory cells. However, in chronic infections, T cells drastically lose effector functions before acquiring a memory phenotype. Chronic infections can be categorized into infections where viremia is controlled and protective memory cells are maintained as in the case of EBV and CMV infections, or where the virus persists and memory cells are exhausted and disrupted as in the case of human immunodeficiency virus infection. In this review, we will discuss the different phenotypical and functional characteristics of memory cells subsets, the importance of the role they play during acute and chronic infections, and the mechanisms behind their effectiveness and persistence. [ABSTRACT FROM AUTHOR]

The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1–PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8+ T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8+ T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8+ T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8+ T cells. Notably, cytomegalovirus (CMV)-specific CD8+ T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8+ T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8+ T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8+ repertoire. [ABSTRACT FROM AUTHOR]

HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4+ T cells. CCR6+ T cells have the potential to migrate into the GALT via the gut-homing integrin α4β7, a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β7 are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6+ T cell permissiveness to infection. We demonstrated that β7-R6+ and β7+R6+ compared with β7-R6- and β7+R6- T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α4 and β7 coexpression in both CCR6+ and CCR6- T cells, but increased HIV permissiveness selectively in CCR6+ T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin β7, is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β7 to regulate cell migration into the GALT and bind HIV-gp120, CCR6+ T cells coexpressing integrin β7 and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6+ T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6+ T cells. [ABSTRACT FROM AUTHOR]

Abstract: Lymph nodes (LNs) represent the principal site where antigen-specific memory T- and B-cell responses are primed and differentiated into memory and effector cells. During chronic viral infections such as HIV, these lymphoid tissues undergo substantial structural changes. These changes are mostly caused by an imbalanced cytokine milieu, hyper-immune activation and collagen deposition leading to fibrotic LNs. The structural integrity of the LNs is essential to prime and maintain memory responses. Because cellular signalling events both up- and down-stream of FOXO3a are critical to the generation and the maintenance of lymphocyte memory, this review will focus on the interplay between the deregulation of the immune system caused by the virus and its impact on FOXO3a. [Copyright &y& Elsevier]