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Expression, and T Cell Lineage Commitment1
* Institute for Cellular Therapeutics and Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202;
Department of Biochemistry and Molecular Biology,
Experimental Immunology Branch, National Cancer Institute, and
Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
¶ Clinical Research Institute of Montreal, Quebec, Canada;
|| Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107; and
# Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111
T cell differentiation in the thymus is dependent upon signaling
through the TCR and is characterized by the resulting changes in
expression patterns of CD4 and CD8 surface coreceptor molecules.
Although recent studies have characterized the effects of proximal TCR
signaling on T cell differentiation, the downstream integration of
these signals remains largely unknown. The growth factor independence-1
(GFI1) and GFI1B transcriptional repressors may regulate cytokine
signaling pathways to affect lymphocyte growth and survival. In this
study, we show that Gfi1 expression is induced upon
induction of the T cell program. Gfi1B expression is low
and dynamic during T cell development, but is terminated in mature
thymocytes. Transgenic expression of GFI1 and GFI1B in T cells allowed
us to determine the functional consequences of constitutive expression.
GFI1 potentiates response to TCR stimulation and IL-2, whereas
GFI1B-transgenic T cells are defective in T cell activation. Moreover,
GFI1B-transgenic thymocytes display reduced expression of the
late-activation marker IL-7R
, and a decrease in
CD4-8+ single-positive T cells that can
be mitigated by transgenic expression of BCL2 or GFI1. These data show
that GFI1 and GFI1B are functionally unique, and implicate a role for
GFI1 in the integration of activation and survival
signals.
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