ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28

Abstract

otherwise fatal overstimulation of the lymphoid system 6-9 . Here we report the identification of a third member of this family of molecules, inducible co-stimulator (ICOS), which is a homodimeric protein of relative molecular mass 55,000-60,000 (M r 55K-60K). Matching CD28 in potency, ICOS enhances all basic Tcell responses to a foreign antigen, namely proliferation, secretion of lymphokines, upregulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. Unlike the constitutively expressed CD28, ICOS has to be de novo induced on the T-cell surface, does not upregulate the production of interleukin-2, but superinduces the synthesis of interleukin-10, a B-cell-differentiation factor. In vivo, ICOS is highly expressed on tonsillar T cells, which are closely associated with B cells in the apical light zone of germinal centres, the site of terminal B-cell maturation. Our results indicate that ICOS is another major regulator of the adaptive immune system.We identified ICOS by generating monoclonal antibodies against activated human T cells. The ICOS-specific monoclonal antibody F44 did not react with resting human peripheral-blood T cells, but stained CD4 + and CD8 + T lymphocytes that had been activated by stimulation of the T-cell antigen receptor (TCR) complex (Fig. 1a). No signal was detected on resting or appropriately activated B cells, monocytes, natural killer cells, granulocytes, dendritic cells or platelets (data not shown). Immunoprecipitations using monoclonal Figure 1 Identification, purification and cloning of ICOS. a, Expression of ICOS on human T cells after 36 h of stimulation.Peripheral-blood CD4 + or CD8 + T cells were left untreated or were stimulated with the solid-phase-bound anti-CD3 monoclonal antibody OKT 3 (1:1,000 dilution of ascites), and were analysed by flow cytometry using the fluorescein isothiocyanate (FITC)-labelled monoclonal antibody F44. At 14 h after stimulation, ICOS could not yet be detected on CD8 + T cells, whereas CD4 + T cells expressed levels of ICOS that were similar to those expressed after 36 h (data not shown). The background signal obtained with the isotype-control monoclonal antibody MOPC-21 (Sigma) is shown in black. Stimulation by phorbol-12-myristate-13-acetate (PMA) and ionomycin led to the expression of ICOS on most CD4 + and CD8 + T cells (data not shown). b, Structure of the homodimeric ICOS protein. ICOS protein was immunoprecipitated from surface-iodinated MOLT-4V cells with monoclonal antibody F44 and separated by two-dimensional (nonreducing/reducing) SDS-PAGE. Numbers at the top and right side of the gel are M r values. The 55K-60K protein species on the diagonal corresponds to residual dimeric ICOS, which was not reduced by the in-gel reducing procedure required for the twodimensional SDS-PAGE (a full reduction of this species was routinely observed in onedimensional SDS-PAGE; data not shown). Identical data were obtained with iodinated activated primary T cells (data not shown). c, ICOS mRNA expression...

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.…”

Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease

“…41 CD28 enhances T-cell functions essential for effective antigen-specific immune responses, whereas CTLA-4 counterbalances the CD28-mediated signals and thus prevents overstimulation of the lymphoid system. 41 A newer member of this family of costimulatory receptors, 'inducible costimulator' (ICOS), was identified by Hutloff et al 42 Unlike the constitutively expressed CD28, ICOS is induced on the T-cell surface and functions to predominantly upregulate interleukin (IL)-4 as opposed to IL-2. 43 Recent sequence analysis demonstrated that the CD28, CTLA-4, and ICOS genes locate telomerically in this order in B230-kb region on chromosome 2q33.…”

LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell‐dependent B cell terminal differentiation

“…In addition to stimulation by TNF/TNFR family members, interaction of ICOS [4], which is a member of the B7 family of costimulatory molecules, with its ligand [5] has also an important role in B cell physiology. ICOS is expressed on both CD4 + and CD8 + activated T lymphocytes [6]. ICOS is essential for T cell-dependent B cell responses [7][8][9] and the GC reactions [10,11].…”