title: High eomesodermin expression among CD57+ CD8+ T cells identifies a CD8+ T cell subset associated with viral control during chronic human immunodeficiency virus infection.
abstract: During HIV infection, increased CD57 expression among CD8(+) T cells has been associated with immune senescence and defective immune responses. Interestingly, CD57-expressing CD8(+) T cells exhibit a dual profile, being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point toward a positive role of CD57-expressing CD8(+) T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57-expressing CD8(+) T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T box transcription factor which determines, coordinately with T-bet, effector and memory CD8(+) T cell differentiation. We defined in healthy donors two functionally distinct CD57-expressing CD8(+) T cell subsets exhibiting different levels of EOMES expression: EOMES(hi) CD57(+) and EOMES(int) CD57(+) CD8(+) T cells. EOMES(hi) CD57(+) cells exhibited low cytotoxic activity but preserved proliferative capacity and interleukin 7 (IL-7) receptor expression, whereas EOMES(int) CD57(+) cells exhibited obvious cytotoxic functions and a more terminally differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy, and HIV controllers; we demonstrated a higher percentage of CD57-expressing cells in all HIV-infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi) CD57(+) cells among HIV-specific and nonspecific CD8(+) T cells from HIV controllers than in aviremic antiretroviral-treated patients and viremic patients. Importantly, such a peculiar non-terminally differentiated EOMES(hi) CD57(+) phenotypic profile was associated with viral control. Importance: This study demonstrates that functional heterogeneity exists among CD57-expressing CD8 T cells, which include both terminally differentiated, highly cytotoxic EOMES(int) CD57(+) CD8(+) T cells and less differentiated EOMES(hi) CD57(+) CD8 T cells, which do not exhibit immediate cytotoxic functions but present high proliferative capacity. Interestingly, HIV controllers present a high proportion of EOMES(hi) CD57 cells among CD57-expressing HIV-specific CD8 T cells compared to both long-term viremic and aviremic antiretroviral therapy (ART)-treated patients, suggesting a beneficial role for this cell subset in viral control.
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France Division of Hematology, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Federico
authors.initials: F
authors.lastname: Simonetta
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Hua
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lécuroux
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France.
authors.forename: Sandie
authors.initials: S
authors.lastname: Gérard
authors.affiliation: INSERM UMR-S 1018, Centre d'études en santé publique, Le Kremlin-Bicêtre, France.
authors.forename: Faroudy
authors.initials: F
authors.lastname: Boufassa
authors.affiliation: Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
authors.forename: Asier
authors.initials: A
authors.lastname: Sáez-Cirión
authors.affiliation: Institut Pasteur, Unité de Régulation des Infections Rétrovirales, Paris, France.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pancino
authors.affiliation: Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Immunologie clinique, Le Kremlin-Bicêtre, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Goujard
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Immunologie clinique, Le Kremlin-Bicêtre, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lambotte
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Venet
authors.affiliation: INSERM, U1012, Le Kremlin-Bicêtre, France Université Paris-Sud, UMR-S1012, Le Kremlin-Bicêtre, France christine.bourgeois@u-psud.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Bourgeois
mesh_terms: D000328:Adult; D018959:CD57 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D006801:Humans; D008875:Middle Aged; D020825:T-Box Domain Proteins / Q000378:metabolism*
chemical_list: D018959:CD57 Antigens; C491199:EOMES protein, human; D020825:T-Box Domain Proteins
references.citation: Blood. 2012 May 24;119(21):4928-38
references.pmid: 22490682
references.citation: Immunity. 2007 Aug;27(2):281-95
references.pmid: 17723218
references.citation: Blood. 2008 Nov 1;112(9):3679-87
references.pmid: 18728248
references.citation: J Immunol. 2010 Nov 1;185(9):4988-92
references.pmid: 20935204
references.citation: J Immunol. 2009 Jul 15;183(2):1120-32
references.pmid: 19564339
references.citation: Clin Infect Dis. 2005 Oct 1;41(7):1053-6
references.pmid: 16142675
references.citation: Science. 2008 Jul 18;321(5887):408-11
references.pmid: 18635804
references.citation: Nat Immunol. 2002 Nov;3(11):1061-8
references.pmid: 12368910
references.citation: PLoS Pathog. 2010 May 27;6(5):e1000917
references.pmid: 20523897
references.citation: AIDS. 2013 Jul 31;27(12):1867-77
references.pmid: 23965471
references.citation: Blood. 2003 Apr 1;101(7):2711-20
references.pmid: 12433688
references.citation: Science. 2003 Nov 7;302(5647):1041-3
references.pmid: 14605368
references.citation: J Leukoc Biol. 2009 Jan;85(1):88-97
references.pmid: 18820174
references.citation: PLoS One. 2014 Feb 27;9(2):e89444
references.pmid: 24586783
references.citation: J Exp Med. 2009 Jan 16;206(1):51-9
references.pmid: 19139168
references.citation: J Infect Dis. 2014 Aug 1;210(3):374-82
references.pmid: 24585893
references.citation: J Infect Dis. 1985 Mar;151(3):555-9
references.pmid: 3156193
references.citation: Nat Immunol. 2005 Dec;6(12):1236-44
references.pmid: 16273099
references.citation: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7239-44
references.pmid: 15872023
references.citation: J Acquir Immune Defic Syndr. 2012 Apr 15;59(5):427-37
references.pmid: 22240463
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15818-23
references.pmid: 14673093
references.citation: Immunity. 2010 Jan 29;32(1):67-78
references.pmid: 20060330
references.citation: J Exp Med. 2007 Sep 3;204(9):2015-21
references.pmid: 17698591
references.citation: J Immunol. 2006 Oct 15;177(8):5145-54
references.pmid: 17015699
references.citation: Blood. 2011 Apr 7;117(14):3799-808
references.pmid: 21289310
references.citation: J Immunol. 2013 Apr 1;190(7):3207-15
references.pmid: 23455505
references.citation: Blood. 2006 Jun 15;107(12):4781-9
references.pmid: 16467198
references.citation: Science. 2012 Nov 30;338(6111):1220-5
references.pmid: 23197535
references.citation: J Virol. 2012 Dec;86(24):13679-88
references.pmid: 23055552
references.citation: J Leukoc Biol. 2013 Jun;93(6):825-36
references.pmid: 23440501
references.citation: Mech Ageing Dev. 2000 Dec 20;121(1-3):77-88
references.pmid: 11164462
references.citation: PLoS Biol. 2004 Feb;2(2):E20
references.pmid: 14966528