Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation.
Signaling via the T-cell receptor complex is necessary but not sufficient to induce antigen-specific T lymphocytes to expand clonally. To proliferate, T cells must receive one or more costimulatory signals provided by antigen presenting cells (APCs). One such critical costimulatory signal is delivered by the CD28/CTLA-4 counterreceptor, B7, expressed on APCs. B7 costimulation induces CD28 signaling, resulting in interleukin 2 (IL-2) secretion, and T-cell proliferation. Conversely, T-cell receptor signaling in the absence of B7 costimulation results in induction of antigen-specific tolerance. Here, we show that activated human B lymphocytes express two additional CTLA-4 counterreceptors also capable of providing T-cell costimulation. At 24 hr postactivation, B cells express a CTLA-4 counterreceptor not recognized by anti-B7 or -BB-1 monoclonal antibodies (mAbs), which induces detectable IL-2 secretion and T-cell proliferation. At 48 and 72 hr postactivation, B cells express both B7 and a third CTLA-4 counterreceptor identified by the anti-BB-1 mAb. BB-1 appears to be a molecule distinct from B7 by its expression on B7- cells and its capacity to induce T cells to proliferate without significant accumulation of IL-2. As observed for B7, costimulatory signals mediated by these alternative CTLA-4/CD28 counterreceptors are likely to be essential for generation of an immune response and their absence may result in antigen-specific tolerance. We propose the following terminology for these CTLA-4 counterreceptors: (i) B7, B7-1; (ii) early CTLA-4 binding counterreceptor, B7-2; and (iii) BB-1, B7-3.
Boussiotis
V A
VA
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA.
Freeman
G J
GJ
Gribben
J G
JG
Daley
J
J
Gray
G
G
Nadler
L M
LM
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D060908:CTLA-4 Antigen; D005434:Flow Cytometry; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D011947:Receptors, Antigen, B-Cell; D011971:Receptors, Immunologic; D000069594:Abatacept