Mouse Inducible Costimulatory Molecule (ICOS) Expression Is Enhanced by CD28 Costimulation and Regulates Differentiation of CD4+ T Cells

Abstract

The inducible costimulatory (ICOS) molecule is expressed by activated T cells and has homology to CD28 and CD152. ICOS binds B7h, a molecule expressed by APC with homology to CD80 and CD86. To investigate regulation of ICOS expression and its role in Th responses we developed anti-mouse ICOS mAbs and ICOS-Ig fusion protein. Little ICOS is expressed by freshly isolated mouse T cells, but ICOS is rapidly up-regulated on most CD4+ and CD8+ T cells following stimulation of the TCR. Strikingly, ICOS up-regulation is significantly reduced in the absence of CD80 and CD86 and can be restored by CD28 stimulation, suggesting that CD28-CD80/CD86 interactions may optimize ICOS expression. Interestingly, TCR-transgenic T cells differentiated into Th2 expressed significantly more ICOS than cells differentiated into Th1. We used two methods to investigate the role of ICOS in activation of CD4+ T cells. First, CD4+ cells were stimulated with beads coated with anti-CD3 and either B7h-Ig fusion protein or control Ig fusion protein. ICOS stimulation enhanced proliferation of CD4+ cells and production of IFN-γ, IL-4, and IL-10, but not IL-2. Second, TCR-transgenic CD4+ T cells were stimulated with peptide and APC in the presence of ICOS-Ig or control Ig. When the ICOS:B7h interaction was blocked by ICOS-Ig, CD4+ T cells produced more IFN-γ and less IL-4 and IL-10 than CD4+ cells differentiated with control Ig. These results demonstrate that ICOS stimulation is important in T cell activation and that ICOS may have a particularly important role in development of Th2 cells.

B cells alter the phenotype and function of follicular‐homing CXCR5+ T cells

“…The IL-10-secreting phenotype was stably maintained during T cell cloning, but secretion was, to a large extent, dependent on ICOS signaling, which is in agreement with previous reports [28][29][30][31]. Of note, studies in ICOS-deficient mice have revealed a key role for this costimulatory molecule in Tdependent B cell responses [24,25].…”

“…Previous studies have identified ICOS as an important regulator of IL-10 production [28][29][30][31], and as shown in Fig. 2, expression of this costimulatory molecule was maintained on T FH cells during co-culture with B cells.…”

“…Furthermore, B cells express the ICOS ligand (ICOS-L) [32], and thus, B cells present amongst feeder cells may induce ICOS signaling in T cell clones, leading to effective T cell priming and the ability to secrete IL-10 in response to subsequent PMA + ionomycin stimulation. To test this possibility, a panel of five representative clones with midto-high-range IL-10 production were activated with PHA and feeder cells for 3 days in the presence or absence of an ICOS-Fc fusion protein designed to bind ICOS-L and to thereby block ICOS function [29,30] (Fig. 5b).…”

Interaction Between ICOS-B7RP1 and B7-CD28 Costimulatory Pathways in Alloimmune Responses In Vivo

“…However, the interactions between the different pathways and their interdependence on each other are only now becoming clear. This is especially true for the ICOS-B7RP1, B7-CD28/CTLA4 and CD40-CD154 pathways (26,27,34). For example, T-cell ICOS up-regulation is reduced in the absence of B7.1 and B7.2, but is restored following CD28 stimulation (26), whereas CTLA4 ligation blocks ICOS costimulation by preventing cell-surface expression and downstream second signals (27).…”

Concanavalin A-mediated T cell proliferation is regulated by herpes virus entry mediator costimulatory molecule

“…HVEM binds to LIGHT, augmenting T cell proliferation and IFN-γ production (Harrop et al 1998;Tamada et al 2000), whereas its binding to BTLA and CD160 negatively regulates T cell proliferation (Cai et al 2008;Sedy et al 2005). ICOS also enhances T cell activation, although it seems to be more important for differentiation of activated T cells (McAdam et al 2000). On the other hand, CD40 is expressed on APCs, while its ligand CD40L is expressed on activated T cells.…”