Tumor necrosis factor-alpha regulates the expression of inducible costimulator receptor ligand on CD34(+) progenitor cells during differentiation into antigen presenting cells

The inducible costimulator receptor (ICOS) is a third member of the CD28 re ceptor family that regulates T cell activation and function. ICOS binds to a newly identified ligand on antigen presenting cells different from the CD 152 ligands CD80 and CD86. We used soluble ICOSIg and a newly developed mur ine anti-human ICOS ligand (ICOSL) monoclonal antibody to further character ize the ICOSL during ontogeny of antigen presenting cells. In a previous st udy, we found that ICOSL is expressed on monocytes, dendritic cells, and B cells. To define when ICOSL is first expressed on myeloid antigen presentin g cells, we examined ICOSL expression on CD34(+) cells in bone marrow. We f ound that CD34(bright) cells regardless of their myeloid commitment were IC OSL-, whereas ICOSL was first expressed when CD34 expression diminished and the myeloid marker CD33 appeared. However, acute myeloid leukemia cells we re 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 progen itor cells that did not constitutively express ICOSL but were induced to ex press ICOSL within 12 h after granulocyte/macrophage colony-stimulating fac tor/tumor necrosis factor alpha (TNF-alpha) stimulation. Interestingly, ICO SL 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 e arly differentiation marker along the monocytic/ dendritic maturation pathw ay. Induction of ICOSL was dependent on TNF-a and was regulated via NF-kapp aB as revealed by use of inhibitors specific for I kappaB alpha phosphoryla tion such as BAY 11-7082 and BAY 11-7085. The antigen presenting capacity o f TNF-alpha stimulated CD34(+) cells was strongly inhibited by ICOSIg fusio n proteins or by NF-kappaB inhibition. Thus, TNF-alpha -induced ICOSL expre ssion seemed to be functionally important for the costimulatory capacity of CD34(+) hematopoietic progenitor cells.