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*
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and
Department of Oncology and Surgical Sciences, Oncology Section, Azienda Ospedaliera, Padova, Italy
CD11b+Gr-1+ myeloid suppressor cells (MSC)
accumulate in lymphoid organs under conditions of intense immune stress
where they inhibit T and B cell function. We recently described the
generation of immortalized MSC lines that provide a homogeneous source
of suppressor cells for dissecting the mechanism of suppression. In
this study we show that the MSC lines potently block in vitro
proliferation of T cells stimulated with either mitogen or antigenic
peptide, with as few as 3% of MSC cells causing complete suppression.
Inhibition of mitogenic and peptide-specific responses is not
associated with a loss in IL-2 production or inability to up-modulate
the early activation markers, CD69 and CD25, but results in direct
impairment of the three IL-2R signaling pathways, as demonstrated by
the lack of Janus kinase 3, STAT5, extracellular
signal-regulated kinase, and Akt phosphorylation in response to IL-2.
Suppression is mediated by and requires NO, which is secreted by MSC in
response to signals from activated T cells, including IFN-
and
a contact-dependent stimulus. Experiments with inducible NO synthase
knockout mice demonstrated that the inhibition of T cell proliferation
by CD11b+Gr-1+ cells in the spleens of
immunosuppressed mice is also dependent upon NO, indicating that the
MSC lines accurately represent their normal counterparts. The
distinctive capacity of MSC to generate suppressive signals when
encountering activated T cells defines a specialized subset of myeloid
cells that most likely serve a regulatory function during times of
heightened immune activity.
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