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Constitutive A kt1 signals attenuate B ‐cell receptor signaling and proliferation, but enhance B ‐cell migration and effector function

2012; Wiley; Volume: 42; Issue: 12 Linguagem: Inglês

10.1002/eji.201242397

1521-4141

Mandy Pierau, Shin‐Young Na, Narasimhulu Simma, Theresa Lowinus, Alexander Marx, Burkhart Schraven, Ursula Bommhardt,

Immune Cell Function and Interaction

Ligation of the BCR induces a complex signaling network that involves activation of A kt, a family of serine/threonine protein kinases associated with B ‐cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced A kt1 signals on B ‐cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing A kt1 were less responsive to BCR stimuli. This correlated with a decrease in C a 2+ ‐mobilization and proliferation, in an impaired activation of E rk1/2 and mammalian target of rapamycin (m TOR ) kinases and poor mobilization of NFAT c1 and NF ‐κ B /p65 factors. In contrast, activation of STAT 5 and migration of B cells toward the chemokine SDF 1α was found to be enhanced. A kt1 T g mice showed an altered maturation of peritoneal and splenic B 1 B cells and an enhanced production of I g G 1 and I g G 3 upon immunization with the T ‐cell independent A g TNP ‐ F icoll. Furthermore, mice homo‐zygous for T g A kt1 showed a severe block in the maturation of B ‐cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced A kt1 signals modify BCR signaling strength and, thereby, B ‐cell development and effector function.