Tumor Necrosis Factor-α Regulates the Expression of Inducible Costimulator Receptor Ligand on CD34+ Progenitor Cells during Differentiation into Antigen Presenting Cells

Abstract

The inducible costimulator receptor (ICOS) is a third member of the CD28 receptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed murine anti-human ICOS ligand (ICOSL) monoclonal antibody to further characterize the ICOSL during ontogeny of antigen presenting cells. In a previous study, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presenting cells, we examined ICOSL expression on CD34 ؉ cells in bone marrow. We found that CD34 bright cells regardless of their myeloid commitment were ICOSL ؊ , whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared. However, acute myeloid leukemia cells were ICOSL-negative, whereas among B-cell malignancies only some cases of the most mature tumors such as prolymphocytic leukemia and hairy cell leukemia were positive. Next, we investigated purified CD34؉ hematopoietic progenitor cells that did not constitutively express ICOSL but were induced to express ICOSL within 12 h after granulocyte/macrophage colony-stimulating factor/tumor necrosis factor ␣ (TNF-␣) stimulation. Interestingly, ICOSL was induced prior to CD80/CD86 induction on CD34؉ cells so that ICOSL was expressed in the absence of CD80/CD86. This suggests that ICOSL is an early differentiation marker along the monocytic/ dendritic maturation pathway. Induction of ICOSL was dependent on TNF-␣ and was regulated via NF-B as revealed by use of inhibitors specific for IB␣ phosphorylation such as BAY 11-7082 and BAY 11-7085. The antigen presenting capacity of TNF-␣ stimulated CD34 ؉ cells was strongly inhibited by ICOSIg fusion proteins or by NF-B inhibition. Thus, TNF-␣-induced ICOSL expression seemed to be functionally important for the costimulatory capacity of CD34 ؉ hematopoietic progenitor cells.Successful antigen-specific T cell stimulation via the T cell receptor (TCR) 1 -CD3 complex (TCR⅐CD3) requires costimulatory signals by the CD28 receptor family. During this process, CD28 or CD152 (CTLA-4) expressed on T cells is engaged by the ligands CD80 (B7-1) or CD86 (B7-2) expressed on antigen presenting cells (1, 2). The inducible costimulator (ICOS) is a recently defined third member of the CD28 family, but unlike CD28, it is not constitutively expressed on T cells (3). ICOS expression requires the activation of T cells via the TCR⅐CD3 complex. ICOS shows structural homology to CD28 and CD152, but it differs in the MYPPPY homology domain necessary for binding of CD28/CD152 to CD80 or CD86 (4). Engagement of ICOS, like CD28, can mediate potent costimulation of T cells (3,5), and promotes T cell proliferation at levels similar to those observed after CD28 triggering but without the accompanying increase in IL-2 production. Instead, ICOS up-regulates expression of IL-4, IL-5, GM-CSF, IFN-␥, TNF-␣, and IL-10 (3, 6). Blocking t...

Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells – possible implications for the ICOS/ICOS-ligand axis in disease course and resolution

“…Importantly, the up-regulation of ICOS-L on human DCs, especially plasmacytoid DCs (pDCs), has already been shown to drive the generation of IL-10-producing T regs [26,28]. Furthermore, the up-regulation of ICOS-L on monocytes/DCs could be induced by inflammatory cytokines such as IFN-g [51], and possibly TNF-a [52], both potent cytokines implicated in sarcoidosis pathogenesis [5,53]. Notably, inflammatory cytokines such as TNF-a and IL-6 can act as a driving factor for the generation of IL-10-producing T regs through ICOS/ICOS-L interactions [27].…”

The phosphoserine-585–dependent pathway of the GM-CSF/IL-3/IL-5 receptors mediates hematopoietic cell survival through activation of NF-κB and induction of bcl-2

“…[34][35][36] Inhibition of NF-B activity by SN50, BAY 11-7082, and BAY 11-7085 blocked the ability of GM-CSF to promote cell survival in CTL-EN cells ( Figure 6C). No effect on cell survival was observed for the SN50M control peptide.…”

ICOS: A New Costimulatory Ligand/Receptor Pair and Its Role in T-Cell Activion

“…The ligand for ICOS (ICOS-L) shares only ~20% amino acid identity with CD80 and CD86. A soluble form of the ICOS receptor was generated and used, together with a subsequently developed mouse anti-human ICOS-L mAb 13C1 that has been generated by DNA vaccination [17], to characterize the ICOS-L. We found that ICOS-L is expressed on human antigen presenting cells of myeloid origin and on about 40% of peripheral blood CD19 + B cells [18]. Expression of ICOS-L was induced on monocytes after integrin-dependent plastic adhesion and was further upregulated by IFN-γ but not TNF-α.…”