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Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):2702-7. doi: 10.1073/pnas.1520112113. Epub 2016 Feb 23.

CXCL13 is a plasma biomarker of germinal center activity.

Author information

1
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;
2
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;
3
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;
4
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
5
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
6
Neutralizing Antibody Center, International AIDS Vaccine Initiative, La Jolla, CA 92037;
7
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
8
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94304;
9
Department of Surgery, University of California, San Diego, CA 92123; Pediatric Otolaryngology, Rady Children's Hospital-San Diego, San Diego, CA 92123;
10
Department of Surgery, Massachusetts General Hospital, Boston, MA 02114;
11
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114;
12
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710;
13
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;
14
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;
15
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322;
16
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;
17
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;
18
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.
19
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.

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.

KEYWORDS:

CXCL13; HIV; Tfh; antibodies; vaccines

PMID:
26908875
PMCID:
PMC4790995
DOI:
10.1073/pnas.1520112113
[Indexed for MEDLINE]
Free PMC Article

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