Expression of CTLA-4 by human monocytes.
Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a receptor present on T cells that plays a critical role in the downregulation of antigen-activated immune responses. CTLA-4 interacts with the ligands CD80 and CD86 on antigen-presenting cells (APC), and also directs the assembly of inhibitory signalling complexes that lead to quiescence or anergy. In this study, we show that human monocytes constitutively express CTLA-4. About 3% of monocytes expressed CTLA-4 on the cell surface, whereas the intracellular expression was higher and present in about 20% of the monocytes. The sequences of the cDNAs from human monocytes were identical to the sequences of CTLA-4 from T cells. Expression of CTLA-4 was also confirmed in the activated myelomonocytic cell lines U937 and THP-1. Monocytes, but not T cells, activated by interferon (IFN)-gamma also secreted soluble CTLA-4 in vitro. The CTLA-4 expression was upregulated upon treatment with phorbol 12-myristate 13-acetate (PMA) and IFN-gamma. This increased expression could be partially abolished by staurosporine, an inhibitor of protein kinase C (PKC). Ligation of CTLA-4 in the monocyte-like cell-line U937 with antibodies against CTLA-4 partially inhibited the proliferation of cells and the upregulation of cell-surface markers CD86, CD54, HLA-DR and HLA-DQ induced by IFN-gamma and Staphylococcus aureus, Cowan I strain (SAC). Ligation of CTLA-4 suppressed the PMA-stimulated activation of transcription activator protein 1 (AP-1) and nuclear factor (NF)-kappaB in the U937 cell line, indicating the involvement of an inhibitory signal transduction. These data provide the first evidence that CTLA-4 is constitutively expressed by monocytes and thus might be important for the regulation of immune mechanisms associated with monocytes.
Wang
X-B
XB
Immunological Research Unit, CMM, Stockholm, Sweden.
Giscombe
R
R
Yan
Z
Z
Heiden
T
T
Xu
D
D
Lefvert
A K
AK
D000069594:Abatacept; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D003432:Cross-Linking Reagents; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology; D007424:Intracellular Fluid / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020298:U937 Cells
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003432:Cross-Linking Reagents; D018796:Immunoconjugates; D016328:NF-kappa B; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D000069594:Abatacept; D007371:Interferon-gamma; D004247:DNA; D011493:Protein Kinase C