title: B7-CD28 interaction is a late acting co-stimulatory signal for human T cell responses.
abstract: The interaction of CD28 with one of the B7 molecules (CD80 and CD86) on professional antigen-presenting cells (APC) is generally considered as the most important co-stimulatory signal for T cell activation. APC in a resting condition express either no or only low levels of B7 molecules. These are up-regulated as a result of interactions with activated T cells, thus suggesting that B7-CD28 interaction is not required at initiation of T cell activation. To study this issue, we blocked B7-CD28 interaction at various time points after in vitro stimulation of peripheral blood T cells with allogeneic monocytes. Epstein-Barr virus-transformed B cells or soluble antigens. We observed that T cell proliferation and IL-2 production were inhibited by B7-blocking agents (CTLA-4-Ig or anti-B7 mAb) almost to the same degree when added either at initiation of culture or 24 h later. B7-blocking agents still resulted in significant inhibition of allogeneic T cell activation when added after 48 h. Furthermore, when CTLA-4-Ig was added at the start of an allogeneic T cell stimulation, addition of anti-CD28 mAb after 24 h of culture nearly fully restored T cell proliferation to control levels. Finally, we demonstrate that delayed addition of B7-blocking agents together with cyclosporin A 1 day after the onset of culture of T cells with allogeneic B cells is highly efficient to induce energy as evaluated by lack of proliferation, cytotoxic T lymphocyte reactivity and IFN-gamma or IL-5 production upon alloantigen rechallenge. Taken together, our data can explain why B7 expression on APC is not required at the time of initial APC-T cell contact, and suggest that the effect of the CD28 signal indeed consists in prolonging IL-2 production and amplifying T cell responses, rather than in providing a critical co-stimulatory signal at the time of initial TCR triggering.
authors.affiliation: Department of Pathophysiology, Catholic University of Leuven, Belgium.
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Zhang
authors.forename: R J
authors.initials: RJ
authors.lastname: Joost van Neerven
authors.forename: S W
authors.initials: SW
authors.lastname: Van Gool
authors.forename: L
authors.initials: L
authors.lastname: Coorevits
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: J L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000069594:Abatacept; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002452:Cell Count; D017635:Clonal Anergy; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D018796:Immunoconjugates; D007376:Interleukin-2; D000069594:Abatacept