REL-DEFICIENT T-CELLS EXHIBIT DEFECTS IN PRODUCTION OF INTERLEUKIN-3 AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR

The c-rel protooncogene encodes a subunit of the NF-kappa B-like famil y of transcription factors, Mice lacking Rel are defective in mitogeni c activation of B and T lymphocytes and display impaired humoral immun ity, In an attempt to identify changes in gene expression that accompa ny the T-cell stimulation defects associated with the loss of Rel, we have examined the expression of cell surface activation markers and cy tokine production in mitogen-stimulated Rel(-/-) T cells, The expressi on of cell surface markers including the interleukin 2 receptor alpha (IL-2R alpha) chain (CD25), CD69 and L-selectin (CD62) is normal in mi togen-activated Rel(-/-) T cells, but cytokine production is impaired, In Rel(-/-) splenic T cell cultures stimulated with phorbol 12-myrist ate 13-acetate and ionomycin, the levels of IL-3, IL-5, granulocyte-ma crophage colony-stimulating factor (GM-CSF), tumor necrosis factor alp ha (TNF-alpha), and gamma interferon (IFN-gamma) were only 2- to 3-fol d lower compared with normal T cells, In contrast, anti-CD3 and anti-C D28 stimulated Rel(-/-) T cells, which fail to proliferate, make littl e or no detectable cytokines, Exogenous IL-2, which restitutes the pro liferative response of the anti-CD3- and anti-CD28-treated Rel(-/-) T cells, restores production of IL-5, TNF-alpha, and IFN-gamma, but not IL-3 and GM-CSF expression to approximately normal levels, In contrast to mitogen-activated Rel(-/-) T cells, lipopolysaccharide-stimulated Rel(-/-) macrophages produce higher than normal levels of GM-CSF, Thes e findings establish that Rel can function as an activator or represso r of gene expression and is required by T lymphocytes for production o f IL-3 and GM-CSF.