title: Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity.
abstract: Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b(+) Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25(+) but also by other subphenotypes. We characterized the CD49b(+) Treg cell phenotype, underscoring its similarities with the CD25(+) Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25(+) and CD49b(+) Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10-secreting CD49b(+) Treg cells in arthritis.
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Rita
authors.initials: R
authors.lastname: Vicente
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Quentin
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mausset-Bonnefont
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Chuchana
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Martire
authors.affiliation: University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Maïlys
authors.initials: M
authors.lastname: Cren
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: INSERM U1183, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France; University of Montpellier, 34095 Montpellier, France; and Centre Hospitalier Universitaire Saint Eloi, Institute of Regenerative Medicine and Biotherapies, 34295 Montpellier, France pascale.plence@inserm.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: Louis-Plence
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001168:Arthritis / Q000276:immunology / Q000628:therapy*; D015704:CD4 Antigens / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D020869:Gene Expression Profiling; D053804:Granzymes / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D039001:Integrin alpha Chains / Q000378:metabolism; D039421:Integrin alpha2 / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556062:IL10 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D039001:Integrin alpha Chains; D039421:Integrin alpha2; D053645:Interleukin-2 Receptor alpha Subunit; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; C091367:alpha E integrins; D016753:Interleukin-10; D053804:Granzymes; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse