title: Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus.
abstract: Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4(+) T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4(+) T cells. Ligation of SLAMF3 receptors on SLE CD4(+) T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland dcomte@bidmc.harvard.edu.
authors.forename: Denis
authors.initials: D
authors.lastname: Comte
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Maria P
authors.initials: MP
authors.lastname: Karampetsou
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Bradley
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Masayuki
authors.initials: M
authors.lastname: Mizui
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Michihito
authors.initials: M
authors.lastname: Kono
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Julie R
authors.initials: JR
authors.lastname: Solomon
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.affiliation: Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115;
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation; D016764:Cell Polarity; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C508017:IL2RA protein, human; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; C430423:LY9 protein, human; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: IL-2; SLAMF3; SLE; Treg; autoimmunity