Abstract
B7-H4 has been shown to inhibit T cell proliferation, cytokine production and cell cycle in vitro. B7-H4 deficient mice develop exacerbated disease in the mouse models of Rheumatoid Arthritis (RA), Type 1 Diabetes (T1D) and Experimental Autoimmune Encephalomyelitis (EAE). On the other hand, B7-H4-Ig fusion protein has been documented to assuage the symptoms in mouse models of RA, T1D, and multiple sclerosis in vivo. In the present study, B7-H4-Ig bound to the majority of human peripheral blood monocytes and NK cells, but not to either normal or activated T cells. B7-H4-Ig fusion protein was assayed for its effects in allogeneic mixed lymphocyte culture (MLC) systems. Soluble B7- H4-Ig had no significant effect in the MLC, but with a tendency to promote allogeneic response. Immobilized, but not soluble B7-H4-Ig inhibited plastic bound anti-CD3 mediated activation of T cells. This inhibition however was largely due to B7-H4-Ig mediated displacement of anti-CD3 antibody from the plastic plate. Finally, B7-H4-Ig had no effect on the cytotoxicity mediated by NK and LAK cells in PBMC. Our findings thus caution against the interpretation of suppressive effect observed solely in plate-bound anti-CD3 mediated T cell co-stimulation in vitro.
Highlights
The B7 family member B7-H4, discovered ten years ago, has been shown to inhibit TCR-mediated proliferation, cell-cycle progression and IL-2 production by CD4+ and CD8+ T cells in murine [1,2,3] and human [4]in vitro systems
A soluble form of B7-H4 has been implicated in pathogenesis of rheumatoid arthritis and genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis in mice [11]
The frequencies of T cells (CD3+), B cells (CD19+), NK cells (CD56+) and monocytes (CD14+) are shown in the FACS plot of normal peripheral blood mononuclear cells (PBMC) and day 3 responder cells in an allogeneic two-way mixed lymphocyte culture (MLC) stained with cell type specific antibodies
Summary
The B7 family member B7-H4, discovered ten years ago, has been shown to inhibit TCR-mediated proliferation, cell-cycle progression and IL-2 production by CD4+ and CD8+ T cells in murine [1,2,3] and human [4]in vitro systems. The B7 family member B7-H4, discovered ten years ago, has been shown to inhibit TCR-mediated proliferation, cell-cycle progression and IL-2 production by CD4+ and CD8+ T cells in murine [1,2,3] and human [4]. A number of cancers have been shown to over-express B7-H4 protein, including human ovarian, breast, prostate and lung cancer, renal-cell carcinoma and uterine adenocarcinoma [9]. B7-H4 knockout mice suffer from a more severe experimental diabetes due to increased islet infiltration of Th1 and Th17 cells, while mice overexpressing B7-H4 were protected from diabetes by reducing IFN-production in CD4 T cells, without skewing towards Th2 phenotype or activation of Tregs [12]. The B7-H4 receptor most probably belongs to an unknown member of the co-inhibitory CD28 superfamily that includes BTLA, CTLA-4 and PD-1 [14]
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