title: Calcineurin-dependent negative regulation of CD94/NKG2A expression on naive CD8+ T cells.
abstract: Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL-2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-β) but enhanced by others (IL-6, IL-10, and IL-21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cho
authors.forename: Hee-Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Kylie
authors.initials: K
authors.lastname: Webster
authors.forename: Mainthan
authors.initials: M
authors.lastname: Palendira
authors.forename: Bumsuk
authors.initials: B
authors.lastname: Hahm
authors.forename: Kyu-Sik
authors.initials: KS
authors.lastname: Kim
authors.forename: Cecile
authors.initials: C
authors.lastname: King
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sprent
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019703:Calcineurin / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism*; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; D007376:Interleukin-2; C527057:Klrc1 protein, mouse; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011948:Receptors, Antigen, T-Cell; D019703:Calcineurin