Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue

Marcus Buggert; Son Nguyen; Gonzalo Salgado Montes de Oca; Bertram Bengsch; Samuel Darko; Amy Ransier; Emily R. Roberts; Daniel del Alcazar; Irene Bukh Brody; Laura A. Vella; Lalit Beura; Sathi Wijeyesinghe; Ramin S. Herati; Perla M. Del Rio Estrada; Yuria Ablanedo-Terrazas; Leticia Kuri-Cervantes; Alberto Sada Japp; Sasikanth Manne; Shant Vartanian; Austin Huffman; Johan K. Sandberg; Emma Gostick; Gregory Nadolski; Guido Silvestri; David H. Canaday; David A. Price; Constantinos Petrovas; Laura F. Su; Golnaz Vahedi; Yoav Dori; Ian Frank; Maxim G. Itkin; E. John Wherry; Steven G. Deeks; Ali Naji; Gustavo Reyes-Terán; David Masopust; Daniel C. Douek; Michael R. Betts

doi:10.1126/sciimmunol.aar4526

Identification and characterization of HIV-specific resident memory CD8⁺ T cells in human lymphoid tissue

Marcus Buggert, Son Nguyen, Gonzalo Salgado Montes de Oca, Bertram Bengsch, Samuel Darko, Amy Ransier, Emily R. Roberts, Daniel del Alcazar, Irene Bukh Brody, Laura A. Vella, Lalit Beura, Sathi Wijeyesinghe, Ramin S. Herati, Perla M. Del Rio Estrada, Yuria Ablanedo-Terrazas, Leticia Kuri-Cervantes, Alberto Sada Japp, Sasikanth Manne, Shant Vartanian, Austin HuffmanJohan K. Sandberg, Emma Gostick, Gregory Nadolski, Guido Silvestri, David H. Canaday, David A. Price, Constantinos Petrovas, Laura F. Su, Golnaz Vahedi, Yoav Dori, Ian Frank, Maxim G. Itkin, E. John Wherry, Steven G. Deeks, Ali Naji, Gustavo Reyes-Terán, David Masopust, Daniel C. Douek, Michael R. Betts

Research output: Contribution to journal › Article › peer-review

106 Scopus citations

Abstract

Current paradigms of CD8⁺ T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8⁺ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (T_RMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8⁺ T cells in LTs also resemble T_RMs. Moreover, high frequencies of HIV-specific CD8⁺ T_RMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific T_RMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-T_RMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8⁺ T cell responses resident within LTs.

Original language	English (US)
Article number	eaar4526
Journal	Science Immunology
Volume	3
Issue number	24
DOIs	https://doi.org/10.1126/sciimmunol.aar4526
State	Published - 2018

Bibliographical note

Funding Information:
was supported by R01/R56 grants from the NIH (AI076066, AI118694, and AI106481 to M.R.B.), the Martin Delaney Collaboratory: Towards an HIV1 Cure (BEAT: AI126620; DARE: AI096109 and A127966), the Penn Center for AIDS Research (CFAR) (AI045008), the amfAR Institute for HIV Cure Research (amfAR 109301 to S.G.D.), the University of California, San Francisco/ Gladstone Institute of Virology and Immunology CFAR to the SCOPE cohort (P30 AI027763 to S.G.D.), K22AI112570 to G.V., and the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH (D.C.D.). M.B. is funded through the Swedish Research Council (Dnr 53720146829), Karolinska Institutet, Magnus Bergvall, and Lars Hiertas Stiftelse. D.A.P. is a Welcome Trust Senior Investigator. D.d.A. and L.F.S. were supported by a Medical Research Grant from the W. W. Smith Charitable Trust Foundation and the Penn CFAR Grant. R.S.H. is funded by K08 grant (AI114852). G.R.T. is funded by the Mexican Government (Comisión de Equidad y Género de las Legislaturas LXLXI, y Comisión de Igualdad de Género de la Legislatura LXII de la H. Cámara de Diputados de la República Mexicana).

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Copyright © 2018 The Authors, some rights reserved.

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Buggert, M., Nguyen, S., de Oca, G. S. M., Bengsch, B., Darko, S., Ransier, A., Roberts, E. R., del Alcazar, D., Brody, I. B., Vella, L. A., Beura, L., Wijeyesinghe, S., Herati, R. S., Del Rio Estrada, P. M., Ablanedo-Terrazas, Y., Kuri-Cervantes, L., Japp, A. S., Manne, S., Vartanian, S., ... Betts, M. R. (2018). Identification and characterization of HIV-specific resident memory CD8⁺ T cells in human lymphoid tissue. Science Immunology, 3(24), Article eaar4526. https://doi.org/10.1126/sciimmunol.aar4526

Buggert, M, Nguyen, S, de Oca, GSM, Bengsch, B, Darko, S, Ransier, A, Roberts, ER, del Alcazar, D, Brody, IB, Vella, LA, Beura, L, Wijeyesinghe, S, Herati, RS, Del Rio Estrada, PM, Ablanedo-Terrazas, Y, Kuri-Cervantes, L, Japp, AS, Manne, S, Vartanian, S, Huffman, A, Sandberg, JK, Gostick, E, Nadolski, G, Silvestri, G, Canaday, DH, Price, DA, Petrovas, C, Su, LF, Vahedi, G, Dori, Y, Frank, I, Itkin, MG, John Wherry, E, Deeks, SG, Naji, A, Reyes-Terán, G, Masopust, D, Douek, DC & Betts, MR 2018, 'Identification and characterization of HIV-specific resident memory CD8⁺ T cells in human lymphoid tissue', Science Immunology, vol. 3, no. 24, eaar4526. https://doi.org/10.1126/sciimmunol.aar4526

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title = "Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue",

abstract = "Current paradigms of CD8+ T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs. Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.",

author = "Marcus Buggert and Son Nguyen and {de Oca}, {Gonzalo Salgado Montes} and Bertram Bengsch and Samuel Darko and Amy Ransier and Roberts, {Emily R.} and {del Alcazar}, Daniel and Brody, {Irene Bukh} and Vella, {Laura A.} and Lalit Beura and Sathi Wijeyesinghe and Herati, {Ramin S.} and {Del Rio Estrada}, {Perla M.} and Yuria Ablanedo-Terrazas and Leticia Kuri-Cervantes and Japp, {Alberto Sada} and Sasikanth Manne and Shant Vartanian and Austin Huffman and Sandberg, {Johan K.} and Emma Gostick and Gregory Nadolski and Guido Silvestri and Canaday, {David H.} and Price, {David A.} and Constantinos Petrovas and Su, {Laura F.} and Golnaz Vahedi and Yoav Dori and Ian Frank and Itkin, {Maxim G.} and {John Wherry}, E. and Deeks, {Steven G.} and Ali Naji and Gustavo Reyes-Ter{\'a}n and David Masopust and Douek, {Daniel C.} and Betts, {Michael R.}",

note = "Funding Information: was supported by R01/R56 grants from the NIH (AI076066, AI118694, and AI106481 to M.R.B.), the Martin Delaney Collaboratory: Towards an HIV1 Cure (BEAT: AI126620; DARE: AI096109 and A127966), the Penn Center for AIDS Research (CFAR) (AI045008), the amfAR Institute for HIV Cure Research (amfAR 109301 to S.G.D.), the University of California, San Francisco/ Gladstone Institute of Virology and Immunology CFAR to the SCOPE cohort (P30 AI027763 to S.G.D.), K22AI112570 to G.V., and the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH (D.C.D.). M.B. is funded through the Swedish Research Council (Dnr 53720146829), Karolinska Institutet, Magnus Bergvall, and Lars Hiertas Stiftelse. D.A.P. is a Welcome Trust Senior Investigator. D.d.A. and L.F.S. were supported by a Medical Research Grant from the W. W. Smith Charitable Trust Foundation and the Penn CFAR Grant. R.S.H. is funded by K08 grant (AI114852). G.R.T. is funded by the Mexican Government (Comisi{\'o}n de Equidad y G{\'e}nero de las Legislaturas LXLXI, y Comisi{\'o}n de Igualdad de G{\'e}nero de la Legislatura LXII de la H. C{\'a}mara de Diputados de la Rep{\'u}blica Mexicana). Publisher Copyright: Copyright {\textcopyright} 2018 The Authors, some rights reserved.",

year = "2018",

doi = "10.1126/sciimmunol.aar4526",

language = "English (US)",

volume = "3",

journal = "Science Immunology",

issn = "2470-9468",

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T1 - Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue

AU - Buggert, Marcus

AU - Nguyen, Son

AU - de Oca, Gonzalo Salgado Montes

AU - Bengsch, Bertram

AU - Darko, Samuel

AU - Ransier, Amy

AU - Roberts, Emily R.

AU - del Alcazar, Daniel

AU - Brody, Irene Bukh

AU - Vella, Laura A.

AU - Beura, Lalit

AU - Wijeyesinghe, Sathi

AU - Herati, Ramin S.

AU - Del Rio Estrada, Perla M.

AU - Ablanedo-Terrazas, Yuria

AU - Kuri-Cervantes, Leticia

AU - Japp, Alberto Sada

AU - Manne, Sasikanth

AU - Vartanian, Shant

AU - Huffman, Austin

AU - Sandberg, Johan K.

AU - Gostick, Emma

AU - Nadolski, Gregory

AU - Silvestri, Guido

AU - Canaday, David H.

AU - Price, David A.

AU - Petrovas, Constantinos

AU - Su, Laura F.

AU - Vahedi, Golnaz

AU - Dori, Yoav

AU - Frank, Ian

AU - Itkin, Maxim G.

AU - John Wherry, E.

AU - Deeks, Steven G.

AU - Naji, Ali

AU - Reyes-Terán, Gustavo

AU - Masopust, David

AU - Douek, Daniel C.

AU - Betts, Michael R.

N1 - Funding Information: was supported by R01/R56 grants from the NIH (AI076066, AI118694, and AI106481 to M.R.B.), the Martin Delaney Collaboratory: Towards an HIV1 Cure (BEAT: AI126620; DARE: AI096109 and A127966), the Penn Center for AIDS Research (CFAR) (AI045008), the amfAR Institute for HIV Cure Research (amfAR 109301 to S.G.D.), the University of California, San Francisco/ Gladstone Institute of Virology and Immunology CFAR to the SCOPE cohort (P30 AI027763 to S.G.D.), K22AI112570 to G.V., and the Intramural Program of the National Institute of Allergy and Infectious Diseases, NIH (D.C.D.). M.B. is funded through the Swedish Research Council (Dnr 53720146829), Karolinska Institutet, Magnus Bergvall, and Lars Hiertas Stiftelse. D.A.P. is a Welcome Trust Senior Investigator. D.d.A. and L.F.S. were supported by a Medical Research Grant from the W. W. Smith Charitable Trust Foundation and the Penn CFAR Grant. R.S.H. is funded by K08 grant (AI114852). G.R.T. is funded by the Mexican Government (Comisión de Equidad y Género de las Legislaturas LXLXI, y Comisión de Igualdad de Género de la Legislatura LXII de la H. Cámara de Diputados de la República Mexicana). Publisher Copyright: Copyright © 2018 The Authors, some rights reserved.

PY - 2018

Y1 - 2018

N2 - Current paradigms of CD8+ T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs. Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.

AB - Current paradigms of CD8+ T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs. Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.

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