Constitutive Expression of the B7h Ligand for Inducible Costimulator on Naive B Cells Is Extinguished after Activation by Distinct B Cell Receptor and Interleukin 4 Receptor–mediated Pathways and Can Be Rescued by CD40 Signaling

Abstract

The recently described ligand–receptor pair, B7h–inducible costimulator (ICOS), is critical for germinal center formation and antibody responses. In contrast to the induced expression of the related costimulatory ligands B7.1 and B7.2, B7h is constitutively expressed on naive B cells and is surprisingly extinguished after antigen engagement and interleukin (IL)-4 cytokine signaling. Although signaling through both B cell receptor (BCR) and IL-4 receptor (R) converge on the extinction of B7h mRNA levels, BCR down-regulation occurs through Ca2+ mobilization, whereas IL-4R down-regulation occurs through a distinct Stat6-dependent pathway. During antigen-specific B cell activation, costimulation through CD40 signaling can reverse both BCR- and IL-4R–mediated B7h down-regulation. These data suggest that the CD40–CD40 ligand signaling pathway regulates B7h expression on activated B cells and may control whether antigen-activated B cells can express B7h and costimulate cognate antigen–activated T cells through ICOS.

ICOS-Induced B7h Shedding on B Cells Is Inhibited by TLR7/8 and TLR9

“…Although B7h is highly expressed on naive B cells, B7h is transcriptionally extinguished on B cells following activation through either BCR or IL-4R (26). However, transcription can be reestablished by costimulation through CD40 receptor, suggesting that CD40L expressed on activated T cells also regulates B7h expression.…”

“…We reported previously that expression of B7h on activated B cells is extinguished over several days through shutoff of B7h gene expression (26). Although expression of B7h on activated B cells is thought to be critical for T-dependent Ab responses, activation of B cells through either BCR or IL-4R paradoxically extinguishes B7h mRNA expression.…”

“…During T-dependent Ab responses, ICOS signaling is regulated by limited access to B7h on activated B cells (26). Although B7h is highly expressed on naive B cells, B7h is transcriptionally extinguished on B cells following activation through either BCR or IL-4R (26).…”

“…Both rested effector and activated T cells cultures were subject to complement lysis with a mixture of anti-MHC (28.16.8S and BP107), anti-heat-stable Ag (JD11), and anti-F c R (2.4G2) mAbs. Splenic B cells were purified as described previously (26). For Fig.…”

Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice

“…[28][29][30] ICOS binds specifically to its ligand (ICOS-L, B7-related protein-1[B7RP-1, B7h]), which is constitutively expressed by B cells. 31 The interaction of ICOS with ICOS-L permits terminal differentiation of B cells to antibodysecreting plasma cells. ICOS expression, although readily detectable on resting T cells, rises to levels comparable with those of CD28 after activation of T cells.…”