A role for STAT5A/B in protection of peripheral T-lymphocytes from postactivation apoptosis: Insights from gene expression profiling

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Abstract

Activation of the transcription factors STAT5A and STAT5B by JAK1 and JAK3 tyrosine kinases is a key event in downstream signaling of γc (common gamma chain)-family cytokine receptors in lymphoid cells. STAT5A/B-deficiency in mice causes, among other consequences, a reduced size and altered composition of the peripheral T-cell pool with predominance of an activated or memory-like population (CD4+/CD44high/CD62Llow) and a proliferative deficiency following antigenic stimulation and subsequent IL-2 treatment. To further elucidate the critical function of STAT5A/B in homeostasis and activation of murine naïve peripheral T-lymphocytes, we have analyzed global gene expression of STAT5A/B-deficient versus wild-type splenic T-cells by profiling with high-density oligonucleotide arrays (Affymetrix). Comparison of (1) basal gene expression of untreated peripheral STAT5A/B-deficient and control T-cells and (2) immediate early gene induction upon in vitro stimulation of either population with IL-2 has revealed differential expression of a broad range of genes potentially contributing to the defects of STAT5A/B deficient T-cells. In the context of enhanced apoptotic rates of STAT5A/B−/−-T-cells in vivo and upon TCR-stimulation in culture our data suggest a role for STAT5 in post-activation survival beyond regulation of antiapoptotic Bcl-2 proteins and hence provide new insights into the nature of the late proliferative block in the T-cell compartment caused by STAT5-deficiency.

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