HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control
Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like c...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.912038/full |
| _version_ | 1811237799368589312 |
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| author | Rabiah Fardoos Rabiah Fardoos Sarah K. Nyquist Sarah K. Nyquist Osaretin E. Asowata Samuel W. Kazer Alveera Singh Abigail Ngoepe Jennifer Giandhari Ntombifuthi Mthabela Dirhona Ramjit Samita Singh Farina Karim Søren Buus Frank Anderson J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield Andile L. Sibiya Rishan Bipath Kumeshan Moodley Warren Kuhn Warren Kuhn Bonnie Berger Son Nguyen Tulio de Oliveira Thumbi Ndung’u Thumbi Ndung’u Thumbi Ndung’u Philip Goulder Philip Goulder Philip Goulder Alex K. Shalek Alex K. Shalek Alex K. Shalek Alasdair Leslie Alasdair Leslie Henrik N. Kløverpris Henrik N. Kløverpris Henrik N. Kløverpris |
| author_facet | Rabiah Fardoos Rabiah Fardoos Sarah K. Nyquist Sarah K. Nyquist Osaretin E. Asowata Samuel W. Kazer Alveera Singh Abigail Ngoepe Jennifer Giandhari Ntombifuthi Mthabela Dirhona Ramjit Samita Singh Farina Karim Søren Buus Frank Anderson J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield Andile L. Sibiya Rishan Bipath Kumeshan Moodley Warren Kuhn Warren Kuhn Bonnie Berger Son Nguyen Tulio de Oliveira Thumbi Ndung’u Thumbi Ndung’u Thumbi Ndung’u Philip Goulder Philip Goulder Philip Goulder Alex K. Shalek Alex K. Shalek Alex K. Shalek Alasdair Leslie Alasdair Leslie Henrik N. Kløverpris Henrik N. Kløverpris Henrik N. Kløverpris |
| author_sort | Rabiah Fardoos |
| collection | DOAJ |
| description | Lymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally TRM-like profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs. |
| first_indexed | 2024-04-12T12:30:42Z |
| format | Article |
| id | doaj.art-2214efc1e1c44dd5be878bda8705a958 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T12:30:42Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2214efc1e1c44dd5be878bda8705a9582022-12-22T03:33:03ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.912038912038HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV controlRabiah Fardoos0Rabiah Fardoos1Sarah K. Nyquist2Sarah K. Nyquist3Osaretin E. Asowata4Samuel W. Kazer5Alveera Singh6Abigail Ngoepe7Jennifer Giandhari8Ntombifuthi Mthabela9Dirhona Ramjit10Samita Singh11Farina Karim12Søren Buus13Frank Anderson14J. Zachary Porterfield15J. Zachary Porterfield16J. Zachary Porterfield17J. Zachary Porterfield18Andile L. Sibiya19Rishan Bipath20Kumeshan Moodley21Warren Kuhn22Warren Kuhn23Bonnie Berger24Son Nguyen25Tulio de Oliveira26Thumbi Ndung’u27Thumbi Ndung’u28Thumbi Ndung’u29Philip Goulder30Philip Goulder31Philip Goulder32Alex K. Shalek33Alex K. Shalek34Alex K. Shalek35Alasdair Leslie36Alasdair Leslie37Henrik N. Kløverpris38Henrik N. Kløverpris39Henrik N. Kløverpris40Africa Health Research Institute (AHRI), Durban, South AfricaDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkInstitute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United StatesProgram in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, United StatesAfrica Health Research Institute (AHRI), Durban, South AfricaInstitute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United StatesAfrica Health Research Institute (AHRI), Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, DenmarkDiscipline of General Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South AfricaDepartment of Otolaryngology-Head & Neck Surgery, Division of Infectious Diseases, University of Kentucky, Lexington, KY, United StatesDepartment of Microbiology, Immunology and Molecular Genetics, - Division of Infectious Diseases, University of Kentucky, Lexington, KY, United StatesDepartment of Internal Medicine - Division of Infectious Diseases, University of Kentucky, Lexington, KY, United States0Department of Otorhinolaryngology & Head & Neck Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa1Department of Otorhinolaryngology, King Edward VIII hospital, University of KwaZulu-Natal, Durban, South Africa2Department of Ear Nose and Throat, General Justice Gizenga Mpanza Regional Hospital (Stanger Hospital), University of KwaZulu-Natal, Durban, South Africa0Department of Otorhinolaryngology & Head & Neck Surgery, Inkosi Albert Luthuli Central Hospital, University of KwaZulu-Natal, Durban, South Africa2Department of Ear Nose and Throat, General Justice Gizenga Mpanza Regional Hospital (Stanger Hospital), University of KwaZulu-Natal, Durban, South Africa3Computer Science & Artificial Intelligence Lab and Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United StatesInstitute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United StatesKwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South AfricaAfrica Health Research Institute (AHRI), Durban, South Africa4HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, South Africa5University College London, Division of Infection and Immunity, London, United KingdomAfrica Health Research Institute (AHRI), Durban, South Africa4HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban, South Africa6Department of Paediatrics, University of Oxford, Oxford, United KingdomInstitute for Medical Engineering & Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States7Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States8Ragon Institute of MGH, Harvard, Cambridge, MA, United StatesAfrica Health Research Institute (AHRI), Durban, South Africa5University College London, Division of Infection and Immunity, London, United KingdomAfrica Health Research Institute (AHRI), Durban, South AfricaDepartment of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark5University College London, Division of Infection and Immunity, London, United KingdomLymphoid tissues are an important HIV reservoir site that persists in the face of antiretroviral therapy and natural immunity. Targeting these reservoirs by harnessing the antiviral activity of local tissue-resident memory (TRM) CD8+ T-cells is of great interest, but limited data exist on TRM-like cells within lymph nodes of people living with HIV (PLWH). Here, we studied tonsil CD8+ T-cells obtained from PLWH and uninfected controls from South Africa. We show that these cells are preferentially located outside the germinal centers (GCs), the main reservoir site for HIV, and display a low cytolytic and a transcriptionally TRM-like profile distinct from blood CD8+ T-cells. In PLWH, CD8+ TRM-like cells are expanded and adopt a more cytolytic, activated, and exhausted phenotype not reversed by antiretroviral therapy (ART). This phenotype was enhanced in HIV-specific CD8+ T-cells from tonsils compared to matched blood suggesting a higher antigen burden in tonsils. Single-cell transcriptional and clonotype resolution showed that these HIV-specific CD8+ T-cells in the tonsils express heterogeneous signatures of T-cell activation, clonal expansion, and exhaustion ex-vivo. Interestingly, this signature was absent in a natural HIV controller, who expressed lower PD-1 and CXCR5 levels and reduced transcriptional evidence of T-cell activation, exhaustion, and cytolytic activity. These data provide important insights into lymphoid tissue-derived HIV-specific CD8+ TRM-like phenotypes in settings of HIV remission and highlight their potential for immunotherapy and targeting of the HIV reservoirs.https://www.frontiersin.org/articles/10.3389/fimmu.2022.912038/fullCD8+ TRM cellsHIVPD-1tonsilsexhaustionnatural HIV control |
| spellingShingle | Rabiah Fardoos Rabiah Fardoos Sarah K. Nyquist Sarah K. Nyquist Osaretin E. Asowata Samuel W. Kazer Alveera Singh Abigail Ngoepe Jennifer Giandhari Ntombifuthi Mthabela Dirhona Ramjit Samita Singh Farina Karim Søren Buus Frank Anderson J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield J. Zachary Porterfield Andile L. Sibiya Rishan Bipath Kumeshan Moodley Warren Kuhn Warren Kuhn Bonnie Berger Son Nguyen Tulio de Oliveira Thumbi Ndung’u Thumbi Ndung’u Thumbi Ndung’u Philip Goulder Philip Goulder Philip Goulder Alex K. Shalek Alex K. Shalek Alex K. Shalek Alasdair Leslie Alasdair Leslie Henrik N. Kløverpris Henrik N. Kløverpris Henrik N. Kløverpris HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control Frontiers in Immunology CD8+ TRM cells HIV PD-1 tonsils exhaustion natural HIV control |
| title | HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control |
| title_full | HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control |
| title_fullStr | HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control |
| title_full_unstemmed | HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control |
| title_short | HIV specific CD8+ TRM-like cells in tonsils express exhaustive signatures in the absence of natural HIV control |
| title_sort | hiv specific cd8 trm like cells in tonsils express exhaustive signatures in the absence of natural hiv control |
| topic | CD8+ TRM cells HIV PD-1 tonsils exhaustion natural HIV control |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.912038/full |
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