Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function
Summary: Background: Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown. Methods: We examined immune checkpoint (IC) expression and func...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422004364 |
| _version_ | 1811271414284550144 |
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| author | Elsa Brunet-Ratnasingham Antigoni Morou Mathieu Dubé Julia Niessl Amy E. Baxter Olivier Tastet Nathalie Brassard Gloria Ortega-Delgado Roxanne Charlebois Gordon J. Freeman Cécile Tremblay Jean-Pierre Routy Daniel E. Kaufmann |
| author_facet | Elsa Brunet-Ratnasingham Antigoni Morou Mathieu Dubé Julia Niessl Amy E. Baxter Olivier Tastet Nathalie Brassard Gloria Ortega-Delgado Roxanne Charlebois Gordon J. Freeman Cécile Tremblay Jean-Pierre Routy Daniel E. Kaufmann |
| author_sort | Elsa Brunet-Ratnasingham |
| collection | DOAJ |
| description | Summary: Background: Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown. Methods: We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using activation-induced marker assays. We determined effector functions representative of TFH, TH1, and TH17/TH22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status. Findings: Expression of dysfunction-related molecules, such as transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy associated with infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined functions rather than IC levels: frequencies of cells with TH1- and TH17/TH22-, but not TFH-related functions, increased. Cells co-expressing TH1 and TFH functions showed response to ICB, suggesting that the cell's state rather than function dictates responsiveness to PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation. Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV infection and other diseases. Funding: NIH, CIHR, CFI, FRQS |
| first_indexed | 2024-04-12T22:20:38Z |
| format | Article |
| id | doaj.art-5afb9923fb4d41e4805be2e33fee7a57 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-12T22:20:38Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-5afb9923fb4d41e4805be2e33fee7a572022-12-22T03:14:23ZengElsevierEBioMedicine2352-39642022-10-0184104254Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and functionElsa Brunet-Ratnasingham0Antigoni Morou1Mathieu Dubé2Julia Niessl3Amy E. Baxter4Olivier Tastet5Nathalie Brassard6Gloria Ortega-Delgado7Roxanne Charlebois8Gordon J. Freeman9Cécile Tremblay10Jean-Pierre Routy11Daniel E. Kaufmann12Research Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, CanadaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USAResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, CanadaChronic Viral Illnesses Service and Division of Hematology, McGill University Health Centre, Montreal, Quebec, CanadaResearch Centre of the Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, Canada; Corresponding author.Summary: Background: Immune checkpoint blockade (ICB) partially reverses the dysfunctional state of antigen-specific T cell in chronic infections. However, its impact on the diverse subsets of CD4+ T cells in humans is largely unknown. Methods: We examined immune checkpoint (IC) expression and function in HIV-specific CD4+ T cells of viremic individuals (≥5000 vRNA cp/ml, n = 17) prior to ART and persons with spontaneous (n = 11) or therapy-induced (n = 16) viral suppression (<40 cp/ml). We investigated IC patterns associated with exhaustion-related transcription factors and chemokine receptors using activation-induced marker assays. We determined effector functions representative of TFH, TH1, and TH17/TH22 using RNA flow cytometric fluorescence in situ hybridization (FISH). We compared increase in cytokine expression upon ICB across functions and patient status. Findings: Expression of dysfunction-related molecules, such as transcription factors and ICs PD-1, TIGIT, and CD200, followed a hierarchy associated with infection status and effector profile. In vitro responsiveness to PD-L1 blockade varied with defined functions rather than IC levels: frequencies of cells with TH1- and TH17/TH22-, but not TFH-related functions, increased. Cells co-expressing TH1 and TFH functions showed response to ICB, suggesting that the cell's state rather than function dictates responsiveness to PD-L1 blockade. Response to PD-L1 blockade was strongest in viremic participants and reduced after ART initiation. Interpretation: Our data highlight a polarization-specific regulation of IC expression and differing sensitivities of antigen-specific T helper subsets to PD-1-mediated inhibition. This heterogeneity may direct and constrain ICB efficacy in restoring CD4+ T cell function in HIV infection and other diseases. Funding: NIH, CIHR, CFI, FRQShttp://www.sciencedirect.com/science/article/pii/S2352396422004364HIV-specific CD4+ T cellsT cell dysfunctionImmune checkpoint blockadePD-1TOXCD4+ T cell subsets |
| spellingShingle | Elsa Brunet-Ratnasingham Antigoni Morou Mathieu Dubé Julia Niessl Amy E. Baxter Olivier Tastet Nathalie Brassard Gloria Ortega-Delgado Roxanne Charlebois Gordon J. Freeman Cécile Tremblay Jean-Pierre Routy Daniel E. Kaufmann Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function EBioMedicine HIV-specific CD4+ T cells T cell dysfunction Immune checkpoint blockade PD-1 TOX CD4+ T cell subsets |
| title | Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function |
| title_full | Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function |
| title_fullStr | Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function |
| title_full_unstemmed | Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function |
| title_short | Immune checkpoint expression on HIV-specific CD4+ T cells and response to their blockade are dependent on lineage and function |
| title_sort | immune checkpoint expression on hiv specific cd4 t cells and response to their blockade are dependent on lineage and function |
| topic | HIV-specific CD4+ T cells T cell dysfunction Immune checkpoint blockade PD-1 TOX CD4+ T cell subsets |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422004364 |
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