Terminal Effector CD8 T Cells Defined by an IKZF2 +IL-7R− Transcriptional Signature Express Fc γRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific This information is current as Antibody-Dependent Cellular Cytotoxicity of September 23, 2021. Prossy Naluyima, Kerri G. Lal, Margaret C. Costanzo, Gustavo H. Kijak, Veronica D. Gonzalez, Kim Blom, Leigh Anne Eller, Matthew Creegan, Ting Hong, Dohoon Kim, Thomas C. Quinn, Niklas K. Björkström, Hans-Gustaf Downloaded from Ljunggren, David Serwadda, Elly T. Katabira, Nelson K. Sewankambo, Ronald H. Gray, Jared M. Baeten, Nelson L. Michael, Fred Wabwire-Mangen, Merlin L. Robb, Diane L. Bolton, Johan K. Sandberg and Michael A. Eller J Immunol published online 13 September 2019 http://www.jimmunol.org/ http://www.jimmunol.org/content/early/2019/09/12/jimmun ol.1900422 Supplementary http://www.jimmunol.org/content/suppl/2019/09/12/jimmunol.190042 Material 2.DCSupplemental by guest on September 23, 2021 Why The JI? 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Published September 13, 2019, doi:10.4049/jimmunol.1900422 The Journal of Immunology Terminal Effector CD8 T Cells Defined by an IKZF2+IL-7R2 Transcriptional Signature Express FcgRIIIA, Expand in HIV Infection, and Mediate Potent HIV-Specific Antibody-Dependent Cellular Cytotoxicity Prossy Naluyima,*,†,1 Kerri G. Lal,†,‡,x,1 Margaret C. Costanzo,‡,x Gustavo H. Kijak,‡,x Veronica D. Gonzalez,† Kim Blom,† Leigh Anne Eller,‡,x Matthew Creegan,‡,x Ting Hong,{ Dohoon Kim,‡,x Thomas C. Quinn,‖,# Niklas K. Bjo¨rkstro¨m,† Hans-Gustaf Ljunggren,† David Serwadda,** Elly T. Katabira,†† Nelson K. Sewankambo,†† ‡‡ {,xx,{{ ‡ Ronald H. Gray, Jared M. Baeten, Nelson L. Michael, Fred Wabwire-Mangen,* Downloaded from Merlin L. Robb,‡,x Diane L. Bolton,‡,x Johan K. Sandberg,†,2 and Michael A. Eller‡,x,2 HIV-1 infection expands large populations of late-stage differentiated CD8 T cells that may persist long after viral escape from TCR recognition. In this study, we investigated whether such CD8 T cell populations can perform unconventional innate-like antiviral effector functions. Chronic untreated HIV-1 infection was associated with elevated numbers of CD45RA+CD57+ terminal + effector CD8 T cells expressing FcgRIIIA (CD16). The FcgRIIIA CD8 T cells displayed a distinctive transcriptional profile http://www.jimmunol.org/ between conventional CD8 T cells and NK cells, characterized by high levels of IKZF2 and low expression of IL7R. This transcriptional profile translated into a distinct NKp80+ IL-7Ra2 surface phenotype with high expression of the Helios tran- scription factor. Interestingly, the FcgRIIIA+ CD8 T cells mediated HIV-specific Ab-dependent cellular cytotoxicity (ADCC) activity at levels comparable with NK cells on a per cell basis. The FcgRIIIA+ CD8 T cells were highly activated in a manner that correlated positively with expansion of the CD8 T cell compartment and with plasma levels of soluble mediators of antiviral immunity and inflammation such as IP-10, TNF, IL-6, and TNFRII. The frequency of FcgRIIIA+ CD8 T cells persisted as patients initiated suppressive antiretroviral therapy, although their activation levels declined. These data indicate that terminally differ- entiated effector CD8 T cells acquire enhanced innate cell-like characteristics during chronic viral infection and suggest that HIV- by guest on September 23, 2021 specific ADCC is a function CD8 T cells use to target HIV-infected cells. Furthermore, as the FcgRIIIA+ CD8 T cells persist in treatment, they contribute significantly to the ADCC-capable effector cell pool in patients on antiretroviral therapy. The Journal of Immunology, 2019, 203: 000–000. he exquisite sensitivity and specificity of TCR-mediated with initial viral decline; however, the response fails to completely sensing of infection is central to the function of T cells suppress or clear infection (1–4). Since the initial character- T but can also, in some situations, limit their ability to ization of HIV-specific cytotoxic CD8 T cells in the late 1980s provide effective immunity. This is evident in the context of HIV-1 (5–9), the limitations in their ability to control viral replication infection, in which the appearance of HIV-1–specific T cells coincides and clear infection are evident (10, 11). High mutation rates in *Makerere University Walter Reed Project, Kampala, Uganda; †Center for Infectious Received for publication April 11, 2019. Accepted for publication August 20, 2019. Medicine, Department of Medicine, Karolinska Institutet, 17177 Stockholm, Swe- This work was supported by a cooperative agreement (W81XWH-07-2-0067) be- den; ‡U.S. Military HIV Research Program, Walter Reed Army Institute of Research, x tween the Henry M. Jackson Foundation for the Advancement of Military Medicine Silver Spring, MD 20910; Henry M. Jackson Foundation for the Advancement of { and the U.S. Department of Defense and with an Interagency Agreement (1Y-A1-26- Military Medicine, Bethesda, MD 20817; Department of Global Health, University ‖ 42-07) with the Division of AIDS, National Institute of Allergy and Infectious Dis- of Washington School of Public Health, Seattle, WA 98195; Laboratory of Immuno- eases, National Institutes of Health, the Swedish Research Council, the Swedish regulation, Division of Intramural Research, National Institute of Allergy and Infectious Cancer Society, and the Karolinska Institutet. Sample collection for the Couples Diseases, National Institutes of Health, Bethesda, MD 20852; #School of Medicine, Johns Observational Study was supported by the Bill and Melinda Gates Foundation (Grant Hopkins University, Baltimore, MD 21205; **Rakai Health Sciences Program, Uganda 41185). Virus Research Institute, Entebbe, Uganda; ††Faculty of Medicine, Makerere University College of Health Sciences, Kampala, Uganda; ‡‡Bloomberg School of Public Health, Address correspondence and reprint requests to Dr. Michael A. Eller, U.S. Military Johns Hopkins University, Baltimore, MD 21205; xxDepartment of Medicine, University of HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Washington School of Public Health, Seattle, WA 98195; and {{Department of Epidemi- Avenue, 1N11, Silver Spring, MD 20910. E-mail address: [email protected] ology, University of Washington School of Public Health, Seattle, WA 98195 The online version of this article contains supplemental material. 1The two first authors contributed equally and should both be considered first authors. Abbreviations used in this article: ADCC, Ab-dependent cellular cytotoxicity; ART, 2The two last authors contributed equally and should both be considered senior antiretroviral therapy; COS, Couples Observation Study; Eomes, eomesodermin; authors. FDR, false discovery rate; HCV, hepatitis C virus; KIR, killer Ig-like receptor; MFI, mean fluorescence intensity; PCA, principal component analysis. ORCIDs: 0000-0002-8970-0198 (K.G.L.); 0000-0003-2043-1513 (L.A.E.); 0000- 0002-0404-1315 (T.C.Q.); 0000-0002-0967-076X (N.K.B.); 0000-0003-0908- This article is distributed under the terms of the CC BY 4.0 Unported license. 7387 (H.-G.L.); 0000-0001-9362-053X (N.K.S.); 0000-0001-5882-5548 (N.L.M.); 0000-0003-3949-9649 (M.L.R.); 0000-0002-6275-0750 (J.K.S.); 0000-0003-3905- Copyright Ó 2019 The Authors. 4877 (M.A.E.). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900422 2 TERMINAL EFFECTOR FcgRIIIA+ CD8 T CELLS EXPAND IN HIV HIV-1 contribute to the ability of the virus to escape adaptive Ethics statement T cell responses (3, 12–14). Also, HIV-specific T cells become The study was approved by the following institutional review boards in the functionally impaired during chronic infection, additionally United States and Uganda: the institutional Review Boards of Uganda’s limiting their ability to control viral replication (15–17). Indeed, National Council for Science and Technology and the National AIDS polyfunctional HIV-specific T cell responses are associated with Research Committee, as well as Division of Human Subjects Protection at better disease outcomes compared with those with a narrower the Walter Reed Army Institute of Research. All participants gave written- informed consent, or written-informed consent was obtained from the functional breadth (18–20). In chronic HIV-1 infection, the parent or legal guardian of those aged 17. For samples from the COS in replicating viral quasispecies have, to a large extent, mutated Kampala, Uganda, all participants gave written-informed consent, and away from the originally transmitted viral sequence under T cell ethical approvals for the study were obtained from Uganda’s National selection pressure, and this probably contributes to the accu- Council for Science