CD4(+)CD25(+) T cells facilitate the induction of T cell anergy.
T cell anergy is characterized by the inability of the T cell to produce IL-2 and proliferate. It is reversible by the addition of exogenous IL-2. A similar state of unresponsiveness is observed when the proliferative response of murine CD4(+)CD25(-) T cells is suppressed in vitro by coactivated CD4(+)CD25(+) T cells. We have developed a suppression system that uses beads coated with anti-CD3 and anti-CD28 Abs as surrogate APCs to study the interaction of CD4(+)CD25(+) and CD4(+)CD25(-) T cells in vitro. CD4(+)CD25(+) T cell-induced suppression, in this model, was not abrogated by blocking the B7-CTLA-4 pathway. When the CD4(+)CD25(-) T cells were separated from the CD4(+)CD25(+) suppressor cells after 24 h of coactivation by the Ab-coated beads, the CD4(+)CD25(-) T cells were unable to proliferate or to produce IL-2 upon restimulation. The induction of this anergic phenotype in the CD4(+)CD25(-) T cells correlated with the up-regulated expression of the gene related to anergy in lymphocytes (GRAIL), a novel anergy-related gene that acts as a negative regulator of IL-2 transcription. This system constitutes a novel mechanism of anergy induction in the presence of costimulation.
Ermann
J
J
Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Szanya
V
V
Ford
G S
GS
Paragas
V
V
Fathman
C G
CG
Lejon
K
K
D000069594:Abatacept; D000818:Animals; D000938:Antigen-Presenting Cells; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D060908:CTLA-4 Antigen; D017635:Clonal Anergy / Q000276:immunology*; D018920:Coculture Techniques; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008811:Mice, Inbred DBA; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D000069594:Abatacept