Antigen-presenting T cells induce the development of cytotoxic CD4+ T cells. I. Involvement of the CD80-CD28 adhesion molecules.
The development of cytotoxic CD4+ T lymphocytes that can kill target cells in a MHC class II-restricted manner was evaluated by comparing different APCs. B-lymphoblasts (B-LCL) pulsed with the superantigen staphylococcus enterotoxin B or allogeneic B-lymphoblasts induce CD4+ T cells without cytotoxic activity. In contrast, superantigen-pulsed, MHC class II+ T cell blasts or allogeneic T cell blasts preferentially induce the development of specific, MHC class II-restricted CD4+ cytotoxic effector cells. CD4+ T cell clones generated with T or B cell blasts as APCs (T- or B-APCs) differ in their cytolytic potential, but secrete a similar cytokine pattern. Our data implicate that activated T-APCs preferentially induce a cytotoxic, CD8+ and CD4+ T cell response. Because the density of CD80 expression is lower on activated T-APCs than on B-APCs, we studied the involvement of CD28 and CD80 adhesion molecules in the generation of CD4+ CTLs. Partial blockade of the CD80 molecule with a CTLA4-Ig fusion protein and with specific anti-CD80 mAbs on B-APCs enhanced the generation of CD4+ CTLs. Specific anti-CD86 mAbs, on the contrary, had no effect on the generation of CD4+ CTLs. In contrast, stimulation of CD28, the CD80 counter-receptor, with a cross-linked B7-Ig fusion protein or with an anti-CD28 mAb, inhibited the generation of CD4+ CTLs. Thus, a reduced interaction between CD80 and CD28 may be relevant for the induction of CD4+ CTLs. This shows a new and not yet described function of these adhesion molecules. This induction of a cytotoxic immune response by T cells as APCs may be relevant for the anticlonotypic regulation of T cells and for the depletion of CD4+ T cells in HIV infection.
Mauri
D
D
Institute of Immunology and Allergology, Inselspital, Bern, Switzerland.
Wyss-Coray
T
T
Gallati
H
H
Pichler
W J
WJ
D000069594:Abatacept; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology*; D015704:CD4 Antigens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen; D015815:Cell Adhesion Molecules / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000069594:Abatacept