title: CXCL13 is a plasma biomarker of germinal center activity.
abstract: Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4(+) T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS(+) (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037;
authors.forename: Colin
authors.initials: C
authors.lastname: Havenar-Daughton
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114;
authors.forename: Madelene
authors.initials: M
authors.lastname: Lindqvist
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Wu
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Reiss
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Kayla
authors.initials: K
authors.lastname: Kendric
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
authors.forename: Simon
authors.initials: S
authors.lastname: Bélanger
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Sudhir Pai
authors.initials: SP
authors.lastname: Kasturi
authors.affiliation: Neutralizing Antibody Center, International AIDS Vaccine Initiative, La Jolla, CA 92037;
authors.forename: Elise
authors.initials: E
authors.lastname: Landais
authors.affiliation: Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Rama S
authors.identifier: http://orcid.org/0000-0003-4737-5240
authors.initials: RS
authors.lastname: Akondy
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94304;
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.affiliation: Department of Surgery, University of California, San Diego, CA 92123; Pediatric Otolaryngology, Rady Children's Hospital-San Diego, San Diego, CA 92123;
authors.forename: Marcella
authors.initials: M
authors.lastname: Bothwell
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Parsia A
authors.initials: PA
authors.lastname: Vagefi
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114;
authors.forename: Eileen
authors.initials: E
authors.lastname: Scully
authors.affiliation: Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710;
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94304; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94304;
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.affiliation: Neutralizing Antibody Center, International AIDS Vaccine Initiative, La Jolla, CA 92037; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114; Howard Hughes Medical Institute, Chevy Chase, MD 20815;
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114; Department of Medicine, Université de Montréal, Montreal, QC H2X 0A9, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, QC H2X 0A9, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; shane@lji.org.
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood*; D054382:Chemokine CXCL13 / Q000097:blood* / Q000276:immunology*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology; D008251:Macaca; D008810:Mice, Inbred C57BL; D014611:Vaccination
chemical_list: D015415:Biomarkers; D054382:Chemokine CXCL13
keywords: CXCL13; HIV; Tfh; antibodies; vaccines