Uncovering of Functional Alternative CTLA-4 Counter-Receptor in B7-Deficient Mice

Abstract

B7 delivers a costimulatory signal through CD28, resulting in interleukin-2 secretion and T cell proliferation. Blockade of this pathway results in T cell anergy. The in vivo role of B7 was evaluated with B7-deficient mice. These mice had a 70 percent decrease in costimulation of the response to alloantigen. Despite lacking B7 expression, activated B cells from these mice bound CTLA-4 and GL1 monoclonal antibody, demonstrating that alternative CTLA-4 ligand or ligands exist. These receptors are functionally important because the residual allogenic mixed lymphocyte responses were blocked by CTLA4Ig. Characterization of these CTLA-4 ligands should lead to strategies for manipulating the immune response.

COSTIMULATORY MOLECULE-DEFICIENT DENDRITIC CELL PROGENITORS (MHC CLASS II+, CD80dim, CD86-) PROLONG CARDIAC ALLOGRAFT SURVIVAL IN NONIMMUNOSUPPRESSED RECIPIENTS12

“…Although DC express several other important intercellular adhesion and costimulatory molecules, including CDUa, CD40, CD44, CD48/58, and CD54, B7-2 (CD86) appears to be the major CD28/CTLA-4 ligand and accounts for the costimulation provided by this pathway during in vitro T-cell responses. The early and sustained expression ofB7-2 mRNA (within 8 hr) <before maximal B7-1 expression) in activated murine B cells (30) suggests that it may provide a critical signal involved in the decision between activation or inactivation of T cells within 24 hr of stimula- tion (31,32). Moreover, APC from B7-1 "knockout" mice that express B7-2 are competent APC (30).…”

“…The early and sustained expression ofB7-2 mRNA (within 8 hr) <before maximal B7-1 expression) in activated murine B cells (30) suggests that it may provide a critical signal involved in the decision between activation or inactivation of T cells within 24 hr of stimula- tion (31,32). Moreover, APC from B7-1 "knockout" mice that express B7-2 are competent APC (30). MHC class II+ DC progenitors that are B7-2-may (as is the case with inhibition of B7-2 expression 127]) allow T cell receptor-mediated signaling events to occur, but inhibit the distinct costimulatory signaJ(s) that is necessary for optimal cytokine production and cytokine-dependent T-cell proliferation.…”

BONE MARROW-DERIVED DENDRITIC CELL PROGENITORS (NLDC 145+, MHC CLASS II+, B7-1dim, B7-2−) INDUCE ALLOANTIGEN-SPECIFIC HYPORESPONSIVENESS IN MURINE T LYMPHOCYTES1,2

“…Indeed, in a recent study, anti-CDBO (B7-1) mAbs failed to inhibit human dendritic Langerhans cell-induced alloactivation of T cells (4Jl. Early and sustained expression of B7-2 mRNA (within 8 hr) (before maximal B7-1 expression) in activated murine B cells (42), suggests that it may provide a critical signal (within the first 24 hr) involved in the decision between activation or inactivation of T cells within 24 hr of stimulation (43,44). Moreover, APCs from mice in which the B7-1 gene has been "knocked out" express B7-2 and are competent APCs (42).…”

CD80+Gr-1+ Myeloid Cells Inhibit Development of Antifungal Th1 Immunity in Mice with Candidiasis

“…Briefly, 5 g of total RNA was reverse transcribed into cDNA using Moloney murine leukemia virus reverse transcriptase (Life Technologies, Gaithersburg, MD). The cDNA was then amplified using specific primers for B7 Ig V-like exon, as described (41). Amplifications were performed in 2 mM MgCl 2 , 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 0.2 mM of each deoxynucleotide triphosphate, 1 M of each primer, and 2.5 U AmpliTaq polymerase (PerkinElmer/Cetus, Norwalk, CT).…”