title: Human circulating PD-1+CXCR3-CXCR5+ memory Tfh cells are highly functional and correlate with broadly neutralizing HIV antibody responses.
abstract: The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4⁺ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1⁺CXCR5⁺CD4⁺ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV⁺ individuals.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.forename: Colin
authors.initials: C
authors.lastname: Havenar-Daughton
authors.forename: Elise
authors.initials: E
authors.lastname: Landais
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kroenke
authors.forename: Cecilia L
authors.initials: CL
authors.lastname: Arlehamn
authors.forename: Laura F
authors.initials: LF
authors.lastname: Su
authors.forename: Rafael
authors.initials: R
authors.lastname: Cubas
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: Pascal
authors.initials: P
authors.lastname: Poignard
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000595:Amino Acid Sequence; D057134:Antibodies, Neutralizing / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D015870:Gene Expression; D020869:Gene Expression Profiling; D018858:Germinal Center / Q000276:immunology / Q000473:pathology / Q000821:virology; D015483:HIV Antibodies / Q000096:biosynthesis*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral; D007156:Immunologic Memory; D008969:Molecular Sequence Data; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; C515187:CXCR3 protein, human; C095085:CXCR5 protein, human; D015483:HIV Antibodies; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5
references.citation: Nat Rev Rheumatol. 2012 May 01;8(6):337-47
references.pmid: 22549246
references.citation: Sci Transl Med. 2013 Mar 13;5(176):176ra32
references.pmid: 23486778
references.citation: Immunol Cell Biol. 2009 Nov-Dec;87(8):590-600
references.pmid: 19721453
references.citation: Science. 2009 Aug 21;325(5943):1006-10
references.pmid: 19608860
references.citation: Arthritis Rheum. 2010 Jan;62(1):234-44
references.pmid: 20039395
references.citation: MMWR Morb Mortal Wkly Rep. 2011 Aug 26;60(33):1128-32
references.pmid: 21866086
references.citation: Nat Immunol. 2009 Feb;10(2):167-75
references.pmid: 19098919
references.citation: Cell Host Microbe. 2012 Oct 18;12(4):396-407
references.pmid: 23084910
references.citation: Curr HIV/AIDS Rep. 2012 Mar;9(1):64-72
references.pmid: 22203469
references.citation: Nature. 2013 Apr 25;496(7446):469-76
references.pmid: 23552890
references.citation: Nat Immunol. 2012 Apr 18;13(5):423-7
references.pmid: 22513323
references.citation: J Immunol. 2010 Oct 1;185(7):4042-52
references.pmid: 20826752
references.citation: Immunity. 2011 Jan 28;34(1):108-21
references.pmid: 21215658
references.citation: Immunity. 2012 Sep 21;37(3):412-25
references.pmid: 22999947
references.citation: MMWR Morb Mortal Wkly Rep. 2013 Feb 22;62(7):119-23
references.pmid: 23425960
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4144-9
references.pmid: 12644702
references.citation: Eur J Immunol. 2003 Feb;33(2):474-82
references.pmid: 12645946
references.citation: J Immunol. 2007 Oct 15;179(8):5099-108
references.pmid: 17911595
references.citation: J Virol. 2009 Jul;83(14):7337-48
references.pmid: 19439467
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: Eur J Immunol. 2006 Jul;36(7):1892-903
references.pmid: 16791882
references.citation: Nature. 1999 Oct 14;401(6754):708-12
references.pmid: 10537110
references.citation: J Immunol. 2011 May 15;186(10):5556-68
references.pmid: 21471443
references.citation: Nature. 2012 Nov 15;491(7424):406-12
references.pmid: 23151583
references.citation: Cell. 2013 Mar 28;153(1):126-38
references.pmid: 23540694
references.citation: Nat Med. 2013 Feb;19(2):143-9
references.pmid: 23389614
references.citation: Annu Rev Immunol. 2011;29:621-63
references.pmid: 21314428
references.citation: Nat Immunol. 2011 Jun;12(6):536-43
references.pmid: 21572431
references.citation: J Immunol. 2012 Apr 15;188(8):3734-44
references.pmid: 22427637
references.citation: Immunity. 2011 Nov 23;35(5):671-80
references.pmid: 22118524
references.citation: Blood. 2012 Aug 2;120(5):985-93
references.pmid: 22692510
references.citation: Science. 2009 Oct 9;326(5950):285-9
references.pmid: 19729618
references.citation: Annu Rev Immunol. 2012;30:429-57
references.pmid: 22224772
references.citation: J Clin Invest. 2012 Sep;122(9):3281-94
references.pmid: 22922258
references.citation: Blood. 2004 Oct 1;104(7):1952-60
references.pmid: 15213097
references.citation: J Exp Med. 2012 Jul 2;209(7):1241-53
references.pmid: 22753927
references.citation: Science. 2011 Sep 16;333(6049):1633-7
references.pmid: 21764753
references.citation: Science. 2011 Nov 11;334(6057):825-9
references.pmid: 21960530
references.citation: Immunity. 2009 Sep 18;31(3):457-68
references.pmid: 19631565
references.citation: J Exp Med. 2000 Dec 4;192(11):1545-52
references.pmid: 11104797
references.citation: Proc Natl Acad Sci U S A. 2012 Nov 13;109(46):18921-5
references.pmid: 23100539
references.citation: Immunity. 2012 Jun 29;36(6):986-1002
references.pmid: 22683125
references.citation: PLoS Pathog. 2012 Sep;8(9):e1002913
references.pmid: 22969431
references.citation: Immunity. 2012 Jan 27;36(1):142-52
references.pmid: 22265676
references.citation: Immunity. 2013 Apr 18;38(4):805-17
references.pmid: 23583644
references.citation: Clin Vaccine Immunol. 2010 Jul;17(7):1055-65
references.pmid: 20463105
references.citation: J Exp Med. 2012 Feb 13;209(2):243-50
references.pmid: 22271576
references.citation: J Exp Med. 2012 Sep 24;209(10):1841-52, S1-24
references.pmid: 22987803
references.citation: J Exp Med. 2011 May 9;208(5):987-99
references.pmid: 21536743
references.citation: J Immunol. 2004 Jul 1;173(1):68-78
references.pmid: 15210760
references.citation: Nature. 2011 Sep 22;477(7365):466-70
references.pmid: 21849977
references.citation: Cell. 2010 Nov 12;143(4):592-605
references.pmid: 21074050
references.citation: J Immunol. 2013 Apr 15;190(8):4014-26
references.pmid: 23487426