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

• Type of Material: Article
• Authors: Marcus Buggert, University of Pennsylvania; Son Nguyen, University of Pennsylvania; Gonzalo Salgado-Montes de Oca, Instituto Nacional de Enfermedades Respiratorias; Bertram Bengsch, University of Pennsylvania; Samuel Darko, National Institute of Allergy and Infectious Diseases; Amy Ransier, National Institute of Allergy and Infectious Diseases; Emily R. Roberts, University of Pennsylvania; Daniel del Alcazar, University of Pennsylvania; Irene Bukh Brody, University of Pennsylvania; Laura A. Vella, University of Pennsylvania; Lalit Beura, University of Minnesota; Sathi Wijeyesinghe, University of Minnesota; Ramin S. Herati, University of Pennsylvania; Perla M. Del Rio Estrada, Instituto Nacional de Enfermedades Respiratorias; Yuria Ablanedo-Terrazas, Instituto Nacional de Enfermedades Respiratorias; Leticia Kuri-Cervantes, University of Pennsylvania; Alberto Sada Japp, University of Pennsylvania; Sasikanth Manne, University of Pennsylvania; Shant Vartanian, University of California San Francisco; Austin Huffman, University of Pennsylvania; Johan K. Sandberg, Karolinska University Hospital; Emma Gostick, Cardiff University; Gregory Nadolski, Hospital of the University of Pennsylvania; Guido Silvestri, Emory University; David H. Canaday, Case Western Reserve University; David A. Price, Cardiff University; Constantinos Petrovas, National Institute of Allergy and Infectious Diseases; Laura F. Su, University of Pennsylvania; Golnaz Vahedi, University of Pennsylvania; Yoav Dori, Hospital of the University of Pennsylvania; Ian Frank, University of Pennsylvania; Maxim G. Itkin, Hospital of the University of Pennsylvania; E. John Wherry, University of Pennsylvania; Steven G. Deeks, University of California San Francisco; Ali Naji, University of Pennsylvania; Gustavo Reyes-Teran, Instituto Nacional de Enfermedades Respiratorias; David Masopust, University of Minnesota; Daniel C. Douek, National Institute of Allergy and Infectious Diseases; Michael R. Betts, University of Pennsylvania
• Language: English
• Date: 2018-06-01
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2018 The Authors, some rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1126/sciimmunol.aar4526
• Title of Journal or Parent Work: Science Immunology
• ISSN: 2470-9468
• Volume: 3
• Issue: 24
• Start Page: eaar4526
• End Page: eaar4526
• Grant/Funding Information: D.A.P. is a Welcome Trust Senior Investigator.; R.S.H. by K08 grant (AI114852).; This research was supported by R01/R56 grants from the National Institutes of Health (AI076066, AI118694, and AI106481 to M.R.B.), the Martin Delaney Collaboratory: Towards an HIV-1 Cure (BEAT: AI126620; DARE: AI096109, A127966), the Penn CFAR (AI045008), the amfAR Institute for HIV Cure Research (amfAR 109301 to S.G.D.), the UCSF/Gladstone Institute of Virology & Immunology CFAR to the SCOPE cohort (P30 AI027763 to S.G.D.), and the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (D.C.D).; 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.; M.B. is funded through the Swedish Research Council (Dnr 537–2014-6829), Karolinska Institutet, Magnus Bergvall and Lars Hiertas Stiftelse.; G.R.T. is funded by the Mexican Government (Comisión de Equidad y Género de las legislaturas LX-LXI, y Comisión de Igualdad de Género de la Legislatura LXII de la H. Cámara de Diputados de la República Mexicana).
• Keywords: SUBSETS; INFECTION; Science & Technology; REPLICATION; CUTTING EDGE; RESPONSES; CD4(+); Life Sciences & Biomedicine; NODE; ACTIVATION; FOLLICLES; TRANSCRIPTION; Immunology
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

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.