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Responses in Rhesus Macaques CD4 T Cell − and CXCR5 + CXCR5

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Responses in Rhesus Macaques CD4 T Cell − and CXCR5 + CXCR5 Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5− CD4 T Cell Responses in Rhesus Macaques This information is current as of September 27, 2021. Smita S. Iyer, Sailaja Gangadhara, Blandine Victor, Rosy Gomez, Rahul Basu, Jung Joo Hong, Celia Labranche, David C. Montefiori, Francois Villinger, Bernard Moss and Rama Rao Amara J Immunol 2015; 195:994-1005; Prepublished online 26 June Downloaded from 2015; doi: 10.4049/jimmunol.1500083 http://www.jimmunol.org/content/195/3/994 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2015/06/26/jimmunol.150008 Material 3.DCSupplemental References This article cites 33 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/195/3/994.full#ref-list-1 by guest on September 27, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR52 CD4 T Cell Responses in Rhesus Macaques Smita S. Iyer,* Sailaja Gangadhara,* Blandine Victor,* Rosy Gomez,* Rahul Basu,* Jung Joo Hong,* Celia Labranche,† David C. Montefiori,† Francois Villinger,* Bernard Moss,‡ and Rama Rao Amara*,x The goal of an HIV vaccine is to generate robust and durable protective Ab. Vital to this goal is the induction of CD4+ T follicular helper (TFH) cells. However, very little is known about the TFH response to HIV vaccination and its relative contribution to magnitude and quality of vaccine-elicited Ab titers. In this study, we investigated these questions in the context of a DNA/modified vaccinia virus Ankara SIV vaccine with and without gp140 boost in aluminum hydroxide in rhesus macaques. In addition, we Downloaded from determined the frequency of vaccine-induced CD4+ T cells coexpressing chemokine receptor, CXCR5 (facilitates migration to B cell follicles) in blood and whether these responses were representative of lymph node TFH responses. We show that booster modified vaccinia virus Ankara immunization induced a distinct and transient accumulation of proliferating CXCR5+ and CXCR52 CD4 T cells in blood at day 7 postimmunization, and the frequency of the former but not the latter correlated with TFH and B cell responses in germinal centers of the lymph node. Interestingly, gp140 boost induced a skewing toward CXCR3 http://www.jimmunol.org/ expression on germinal center TFH cells, which was strongly associated with longevity, avidity, and neutralization potential of vaccine-elicited Ab response. However, CXCR3+ cells preferentially expressed the HIV coreceptor CCR5, and vaccine-induced CXCR3+CXCR5+ cells showed a moderate positive association with peak viremia following SIV251 infection. Taken together, our findings demonstrate that vaccine regimens that elicit CXCR3-biased TFH cell responses favor Ab persistence and avidity but may predispose to higher acute viremia in the event of breakthrough infections. The Journal of Immunology, 2015, 195: 994–1005. he induction of robust and long-lived Ab responses forms arise within B cell follicles typically 2–4 wk after immunization the basis of protective immunity elicited by most vaccines and are composed of Ag-specific B cell clones of varying affinity T (1). Ab dynamics following immunization result from that result from rapid B cell proliferation and receptor diversifi- by guest on September 27, 2021 activation of Ag-specific B cells and their subsequent commitment cation. High-affinity clones that successfully engage TCRs on + into two distinct cell fates—extrafollicular plasmablasts or ger- CD4 T follicular helper (TFH) cells within the GCs receive TFH minal center (GC) B cells. Plasmablasts are rapidly proliferating cell help in the form of cytokines such as IL-21, IL-2, and IL-4 Ab-secreting cells (ASCs) within secondary lymphoid organs that and costimulatory signals such as ICOS and CD40L resulting in mainly contribute to peak Ab titers within the first few weeks after their survival and differentiation to plasma cells or memory immunization (1, 2). Long-lived serological memory is estab- B cells (3, 4). lished by GC-derived bone marrow–resident plasma cells. GCs The vital role of TFH cells in the induction of humoral immunity makes them attractive vaccine targets, and characterizing vaccine elicited T cell responses associated with broad and robust Ab *Division of Microbiology and Immunology, Emory Vaccine Center, Yerkes National FH Primate Research Center, Emory University, Atlanta, GA 30329; †Department of titers will provide valuable information for vaccine design. Until Surgery, Duke University, Durham, NC 27705; ‡LaboratoryofViralDiseases,Na- recently, tracking vaccine-elicited TFH cells in humans represented tional Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and xDepartment of Microbiology and Immunology, Emory a challenge because of the belief that TFH cells are exclusively University, Atlanta, GA 30329 localized to the GCs of secondary lymphoid organs. However, Received for publication January 13, 2015. Accepted for publication May 25, 2015. there is some evidence that TFH cells circulate transiently as + + This work was supported in part by National Institutes of Health Grants PO1 CXCR5 CD4 T cells in blood and, based on the expression AI088575 (to R.R.A.), P51 OD011132 (to Yerkes National Primate Research Center), profile of activation markers, are predictive of Ab responses. For P30 AI50409 (to Emory Center for AIDS Research), and HHSN27201100016C (to instance, HIV+ individuals that respond to H1N1 vaccine show D.C.M.). Partial support was also provided by the Division of Intramural Research, + + National Institute of Allergy and Infectious Diseases, National Institutes of Health. expansion of CXCR5 CD4 T cells in the blood (peripheral [p] + Address correspondence and reprint requests to Dr. Rama Rao Amara, Division of TFH), and the frequency of ICOS pTFH cells correlates with Microbiology and Immunology, Emory Vaccine Center, Yerkes National Primate concurrent H1N1 titers (5). Likewise, CCR7loPD-1+ cells within Research Center Room 3024, Emory University, 954 Gatewood Road, Atlanta, GA the pT cell pool are induced after influenza vaccination; this 30329. E-mail address: [email protected] FH subset is overrepresented in patients with autoimmune syndromes The online version of this article contains supplemental material. and highly correlates with anti-dsDNA Abs and disease severity Abbreviations used in this article: alum, aluminum hydroxide; ASC, Ab-secreting cell; DDMM, DNA DNA MVA MVA; GC, germinal center; LN, lymph node; MFI, (6). Taken together, these studies indicate that vaccine-elicited median fluorescence intensity; MVA, modified vaccinia virus Ankara; p, peripheral; TFH cells circulate during the effector response to vaccination, PD, programmed death; SLAM, signaling lymphocyte activation marker; TFH,T these pT cells demonstrate an activated phenotype, and their follicular helper. FH magnitude correlates with vaccine-specific Ab titers generated Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 within a month after vaccination. What is less understood is www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500083 The Journal of Immunology 995 whether pTFH cells are predictive of long-term Ab titers and quality in augmented Ab responses, 14 animals were randomized to receive gp140 Env in alum along with the second MVA (DDMM-Pro). The DNA immu- and how they compare with lymph node (LN) TFH cell responses. Recent studies have underscored the expression of chemokine nogen expressed SIV239 Gag-Pol, Env, Tat, Rev, and coexpressed macaque CD40L and was delivered at 3 mg/dose (10). The MVA immunogen receptors as a key functional attribute of TFH cells (7). Blood expressed SIV239 Gag, Pol, and Env and was delivered at a 108 PFU/dose CXCR5+CD4+ T cells in humans are composed of CXCR3+ and (11, 12). Protein vaccination consisted of 100 mg endotoxin-free SIV239 CXCR32 subsets, which show heterogeneity in B cell helper po- gp140 (Immune Technology), which was premixed with 500 mg alum (2% tential. For instance, induction of CXCR3+ICOS+CXCR5+ pT alhydrogel; InvivoGen) prior to vaccination and was delivered in the thigh FH contralateral to MVA immunization. Briefly, protein and alum were combined cells at day 7 after influenza vaccination predicts increase in Ab in a 1:1 volume ratio and were mixed by rocking at room temperature for 10 titers at day 28 postimmunization (8). In contrast, in HIV-infected min. Prepared inoculum was stored on ice until the time of inoculation. All 2 individuals, frequency of CXCR3 PD-1+CXCR5+ cells is associated immunizations were delivered in PBS i.m. in a single shot in the outer thigh. with the development of neutralizing Abs (9). These data indicate SIV infection that phenotypic characteristics of pTFH cells may be specific to the vaccine/infectious agent and the resulting inflammatory response. In At 6 mo after vaccination, all vaccinated animals were challenged with the context of HIV infection, the data suggest that CXCR3- T cells SIVmac251 intrarectally on a weekly basis for a maximum of 5 wk or until FH detection of plasma viremia above 250 copies/ml for two consecutive may be favorable for induction of Abs. However, this paradigm has weeks. Infection with SIVmac251 (day 8, 7.9.10 virus stock from N.
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