Costimulation of T lymphocytes with integrin ligands intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 induces functional expression of CTLA-4, a second receptor for B7.
Costimulation by the CD28 ligand B7/BB1 plays an important role during T cell proliferation primarily by augmenting synthesis of IL-2 and other cytokines. Resting CD4+ T cells express CD28 but not CTLA-4 on their surface. Costimulation of T cells with ICAM-1 or VCAM-1 induced CTLA-4 expression and up-regulated CD28 expression. CD28 and CTLA-4 were independently distributed on the surface of activated T lymphoblasts. When co-immobilized with anti-TCR mAb both anti-CD28 and anti-CTLA-4 mAb augmented T cell proliferation. Although anti-CD28-mediated augmentation of T cell proliferation was stronger than that seen with anti-CTLA-4 mAb, together these two mAb caused supraadditive augmentation of T cell proliferation. The augmentation of the effects of anti-CD28 mAb by anti-CTLA-4 mAb was greater at low occupancy of CD28 by anti-CD28 mAb. Costimulation of CD28+ CTLA-4+ T cells with anti-CTLA-4 caused three- to fivefold increase in IL-2 production, whereas similar treatment with anti-CD28 caused > 40-fold increase. The costimulatory effect of B7 on primed T cells was partially inhibited by Fab anti-CD28 mAb. Anti-CTLA-4 mAb alone did not inhibit B7-induced response but caused modest increase in the inhibitory effect of anti-CD28 Fab. On integrin-mediated costimulation, Ag-specific CD4+ T cell lines also up-regulated their CTLA-4 expression, and proliferation of these cells was augmented by anti-CTLA-4 mAb. Unlike that of CD28, ligation of CTLA-4 alone failed to mobilize intracellular [Ca2+]. However, coligation of CTLA-4 and TCR induced stronger [Ca2+] response in Ag-specific T cell lines than that seen with TCR alone. These results suggest that integrin-costimulated T cells express CTLA-4 and can be costimulated via CTLA-4. Optimal development of various immune functions may involve combined costimulation via both CD28 and CTLA-4.
Damle
N K
NK
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
Klussman
K
K
Leytze
G
G
Myrdal
S
S
Aruffo
A
A
Ledbetter
J A
JA
Linsley
P S
PS
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis* / Q000502:physiology; D018122:B7-1 Antigen / Q000494:pharmacology; D018106:CD28 Antigens / Q000032:analysis / Q000502:physiology; D060908:CTLA-4 Antigen; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D018796:Immunoconjugates; D016023:Integrins / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1; D008213:Lymphocyte Activation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018796:Immunoconjugates; D016023:Integrins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000069594:Abatacept; D002118:Calcium