title: NKG2A is a marker for acquisition of regulatory function by human CD8+ T cells activated with anti-CD3 antibody.
abstract: Treatment with anti-CD3 mAb modulates immune responses that cause type 1 diabetes and other diseases. CD8+ Tregs can be induced in vitro and in vivo by mAb. However, 1/3 of patients do not respond to drug therapy and in an equal proportion, anti-CD3 mAb does not induce Tregs in vitro. The acquisition of CD8+ Treg activity is a function of the CD8+ cells and not the targets in the assay. To identify markers to differentiate responses of CD8+ Tregs, we analyzed genes differentially expressed in CD8+ T cells of non-responders compared with responders, and found that an inhibitory receptor NKG2A (CD159a) was highly expressed in cells from all non-responders tested. Application of a mAb agonistic to NKG2A during in vitro CD8+ Treg induction by anti-CD3 prevented induction of CD8+ Tregs. CD8+ T cells that are TNFR2+ but NKG2A- are the most potently induced Tregs. The level of NKG2A expression on resting CD8+ T cells inversely correlated with acquisition of regulatory function when activated. We suggest that the induction of human CD8+ Tregs by anti-CD3 mAb is controlled by a negative signaling through NKG2A, and that NKG2A may serve as a negative marker of human CD8+ Tregs.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Ablamunits
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.forename: Paula
authors.initials: P
authors.lastname: Preston-Hurlburt
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology*; D015415:Biomarkers; D017252:CD3 Complex / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation; D046228:Microarray Analysis; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000819:agonists / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D017252:CD3 Complex; D053645:Interleukin-2 Receptor alpha Subunit; D055654:NK Cell Lectin-Like Receptor Subfamily C; D020033:Protein Isoforms; D047889:Receptors, Tumor Necrosis Factor, Type II