title: Paradoxical inhibition of T-cell function in response to CTLA-4 blockade; heterogeneity within the human T-cell population.
abstract: T-cell co-stimulation delivered by the molecules B7-1 or B7-2 through CD28 has a positive effect on T-cell activation, whereas engagement of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by these molecules inhibits activation. In vivo administration to mice of blocking monoclonal antibodies or Fab fragments against CTLA-4 can augment antigen-specific T-cell responses and, thus, therapy with monoclonal antibody against CTLA-4 has potential applications for tumor therapy and enhancement of vaccine immunization. The effects of B7-1 and B7-2 co-stimulation through CD28 depend on the strength of the signal delivered through the T-cell receptor (TCR) and the activation state of T cells during activation. Thus, we sought to determine whether these factors similarly influence the effect of B7-mediated signals delivered through CTLA-4 during T-cell activation. Using freshly isolated human T cells and Fab fragments of a monoclonal antibody against CTLA-4, we demonstrate here that CTLA-4 blockade can enhance or inhibit the clonal expansion of different T cells that respond to the same antigen, depending on both the T-cell activation state and the strength of the T-cell receptor signal delivered during T-cell stimulation. Thus, for whole T-cell populations, blocking a negative signal may paradoxically inhibit immune responses. These results provide a theoretical framework for clinical trials in which co-stimulatory signals are manipulated in an attempt to modulate the immune response in human disease.
authors.affiliation: Committee on Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Anderson
authors.forename: K D
authors.initials: KD
authors.lastname: Bieganowska
authors.forename: A
authors.initials: A
authors.lastname: Bar-Or
authors.forename: E M
authors.initials: EM
authors.lastname: Oliveira
authors.forename: B
authors.initials: B
authors.lastname: Carreno
authors.forename: M
authors.initials: M
authors.lastname: Collins
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D016466:CHO Cells; D060908:CTLA-4 Antigen; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018796:Immunoconjugates; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept