Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions
- PMID: 24352453
- PMCID: PMC3958087
- DOI: 10.1128/JVI.02034-13
Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions
Abstract
Antigen persistence in chronic infections and cancer upregulates inhibitory networks, such as the PD-1 and interleukin-10 (IL-10) pathways, that impair immunity and lead to disease progression. These pathways are attractive targets for immunotherapy, as demonstrated by recent clinical trials of PD-1/PD-L1 blockade in cancer patients. However, in HIV-1 infection not all subjects respond to inhibition of either pathway and the mechanistic interactions between these two networks remain to be better defined. Here we demonstrate that in vitro blockade of PD-L1 and/or IL-10Rα results in markedly different profiles of HIV-1-specific CD4 T cell restoration. Whereas PD-L1 blockade leads to balanced increase in gamma interferon (IFN-γ), IL-2, and IL-13 secretion, IL-10Rα blockade preferentially restores IFN-γ production. In viremic subjects, combined PD-L1/IL-10Rα blockade results in a striking 10-fold increase in IFN-γ secretion by HIV-1-specific CD4 T cells that is not observed in subjects with spontaneous (elite controllers) or therapy-induced control of viral replication. In contrast to the dramatic increase in IFN-γ production, concurrent blockade has a marginal additive effect on IL-2 production, IL-13 secretion, and HIV-1-specific CD4 T cell proliferation. IFN-γ produced by Thelper cells upregulates PD-L1, HLA I/II, and IL-12 expression by monocytes. The effect of combined blockade on IFN-γ was dependent on reciprocal reinforcement through IL-12. These studies provide crucial information on the different immunoregulatory qualities of PD-1 and IL-10 in progressive disease and link exhausted virus-specific CD4 T cells and monocytes in the regulation of IFN-γ and IL-12 secretion.
Importance: Infection with HIV results in most people in uncontrolled viral replication and progressive weakening of the body defenses. In the absence of antiviral therapy, this process results in clinical disease, or AIDS. An important reason why HIV continues to multiply is that a population of white blood cells called CD4 T cells that targets the virus fails to work properly. At least part of this impairment is under the control of inhibitory mechanisms that can be blocked to improve the function of these CD4 T cells. In this report, we show that blocking one or two of the molecules involved, called PD-1 and IL-10, has different effects on the individual functions of these cells and that one is strongly improved. We investigate how these effects are caused by interactions between CD4 T cells and antigen-presenting cells. These observations can have implications for new therapeutic approaches in HIV infection.
Figures
Similar articles
-
CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes.J Virol. 2012 Jun;86(12):6586-94. doi: 10.1128/JVI.06251-11. Epub 2012 Apr 11. J Virol. 2012. PMID: 22496237 Free PMC article.
-
Differential Inhibitory Receptor Expression on T Cells Delineates Functional Capacities in Chronic Viral Infection.J Virol. 2017 Nov 14;91(23):e01263-17. doi: 10.1128/JVI.01263-17. Print 2017 Dec 1. J Virol. 2017. PMID: 28904197 Free PMC article.
-
Regulatory B cells inhibit cytotoxic T lymphocyte (CTL) activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs.PLoS One. 2014 Apr 16;9(4):e92934. doi: 10.1371/journal.pone.0092934. eCollection 2014. PLoS One. 2014. PMID: 24739950 Free PMC article.
-
Gamma-Chain Receptor Cytokines & PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C.Cells. 2021 Mar 3;10(3):538. doi: 10.3390/cells10030538. Cells. 2021. PMID: 33802622 Free PMC article. Review.
-
New expression of PD-L1 on activated CD4+ T cells opens up new opportunities for cell interactions and signaling.Hum Immunol. 2024 Jul;85(4):110831. doi: 10.1016/j.humimm.2024.110831. Epub 2024 Jun 12. Hum Immunol. 2024. PMID: 38870593 Review.
Cited by
-
Artificial antigen-presenting cell system reveals CD28's role in modulating T cell functions during human immunodeficiency virus infection.iScience. 2024 Sep 13;27(10):110947. doi: 10.1016/j.isci.2024.110947. eCollection 2024 Oct 18. iScience. 2024. PMID: 39381752 Free PMC article.
-
The role of CD4+ T cells in tumor and chronic viral immune responses.MedComm (2020). 2023 Oct 10;4(5):e390. doi: 10.1002/mco2.390. eCollection 2023 Oct. MedComm (2020). 2023. PMID: 37829505 Free PMC article. Review.
-
Differential expression of programmed death 1 (PD-1) on various immune cells and its role in human leprosy.Front Immunol. 2023 Apr 21;14:1138145. doi: 10.3389/fimmu.2023.1138145. eCollection 2023. Front Immunol. 2023. PMID: 37153623 Free PMC article.
-
Modulating Immune Response in Viral Infection for Quantitative Forecasts of Drug Efficacy.Pharmaceutics. 2023 Jan 3;15(1):167. doi: 10.3390/pharmaceutics15010167. Pharmaceutics. 2023. PMID: 36678799 Free PMC article. Review.
-
Cellular Senescence in Immunity against Infections.Int J Mol Sci. 2022 Oct 6;23(19):11845. doi: 10.3390/ijms231911845. Int J Mol Sci. 2022. PMID: 36233146 Free PMC article. Review.
References
-
- Wherry EJ. 2011. T cell exhaustion. Nat. Immunol. 12:492–499 - PubMed
-
- Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD. 2007. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8:1246–1254. 10.1038/ni1515 - DOI - PubMed
-
- D'Souza M, Fontenot AP, Mack DG, Lozupone C, Dillon S, Meditz A, Wilson CC, Connick E, Palmer BE. 2007. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. J. Immunol. 179:1979–1987 - PubMed
-
- Kassu A, Marcus RA, D'Souza MB, Kelly-McKnight EA, Golden-Mason L, Akkina R, Fontenot AP, Wilson CC, Palmer BE. 2010. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185:3007–3018. 10.4049/jimmunol.1000156 - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials