Abstract
We, and others, have reported that in the HIV-negative settings, regulatory CD4+CD25highFoxP3+ T cells (Treg) exert differential effects on CD8 subsets, and maintain the memory / effector CD8+ T cells balance, at least in part through the PD-1/PD-L1 pathway. Here we investigated Treg–mediated effects on CD8 responses in chronic HIV infection. As compared to Treg from HIV negative controls (Treg/HIV-), we show that Treg from HIV infected patients (Treg/HIV+) did not significantly inhibit polyclonal autologous CD8+ T cell function indicating either a defect in the suppressive capacity of Treg/HIV+ or a lack of sensitivity of effector T cells in HIV infection. Results showed that Treg/HIV+ inhibited significantly the IFN-γ expression of autologous CD8+ T cells stimulated with recall CMV/EBV/Flu (CEF) antigens, but did not inhibit HIV-Gag–specific CD8+ T cells. In cross-over cultures, we show that Treg/HIV- inhibited significantly the differentiation of either CEF- or Gag-specific CD8+ T cells from HIV infected patients. The expression of PD-1 and PD-L1 was higher on Gag-specific CD8+ T cells as compared to CEF-specific CD8+ T cells, and the expression of these markers did not change significantly after Treg depletion or co-culture with Treg/HIV-, unlike on CEF-specific CD8+ T cells. In summary, we show a defect of Treg/HIV+ in modulating both the differentiation and the expression of PD-1/PD-L1 molecules on HIV-specific CD8 T cells. Our results strongly suggest that this particular defect of Treg might contribute to the exhaustion of HIV-specific T cell responses.
Highlights
CD8 T cells play a crucial role in the control of viral infection
Our results strongly suggest that this particular defect of Treg might contribute to the exhaustion of HIV-specific T cell responses
The phenotype and functional potential of chronically stimulated CD8 T cells differ among viral infections (9).HIV-specific response is characterized by a decreased proliferative capacity of the central memory CD8 T cell pool, incomplete differentiation of effectors with reduced cytotoxic ability, and increased sensitivity to apoptosis as compared to CD8 T cells specific for non-progressive persistent infections, such as EBV or cytomegalovirus (CMV)[10,11].Several studies have suggested a particular role for the programmed cell death-1 (PD-1)/ PD-L1 pathway in the exhaustion of HIV-specific CD8 T cells
Summary
CD8 T cells play a crucial role in the control of viral infection. While several lines of evidence indicate that HIV-specific CD8 T cells are involved in the response to HIV infection[1,2], their failure to clear the virus in the vast majority of infected individuals has not yet been elucidated [3,4,5]. Chronic viral infection with ongoing antigenic stimulation may result in exhaustion of virus-specific T cells due to the engagement of down-regulatory mechanisms. The phenotype and functional potential of chronically stimulated CD8 T cells differ among viral infections (9).HIV-specific response is characterized by a decreased proliferative capacity of the central memory CD8 T cell pool, incomplete differentiation of effectors with reduced cytotoxic ability, and increased sensitivity to apoptosis as compared to CD8 T cells specific for non-progressive persistent infections, such as EBV or cytomegalovirus (CMV)[10,11].Several studies have suggested a particular role for the PD-1/ PD-L1 pathway in the exhaustion of HIV-specific CD8 T cells. PD-1 is upregulated on HIVspecific [12] and simian immunodeficiency virus (SIV)-specific CD8 T cells [13], and the level of PD-1 expression is associated with decreased HIV-specific CD8 T-cell proliferation [14]. A recovery of antigen-specific CD8 T cells from exhaustion has been demonstrated in vivo after blocking the PD-1/PD-L1 interaction in a murine model of LCMV infection, as well as in a SIV-macaque model. [13,16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
