Zfat-deficient CD4⁺ CD8⁺ double-positive thymocytes are susceptible to apoptosis with deregulated activation of p38 and JNK.

Zfat, which is a nuclear protein harboring an AT-hook domain and 18-repeats of C2H2 zinc-finger motif, is highly expressed in immune-related tissues, including the thymus and spleen. T cell specific deletion of the Zfat gene by crossing Zfat(f/f) mice with LckCre mice yields a significant reduction in the number of CD4(+) CD8(+) double-positive (DP) thymocytes. However, physiological role for Zfat in T cell development in the thymus remains unknown. Here, we found that Zfat-deficient DP thymocytes in Zfat(f/f)-LckCre mice were susceptible to apoptosis both at an unstimulated state and in response to T cell receptor (TCR)-stimulation. The phosphorylation levels of p38 and JNK were elevated in Zfat-deficient thymocytes at an unstimulated state with an enhanced phosphorylation of ATF2 and with an over-expression of Gadd45α⋅ On the other hand, the activation of JNK in the Zfat-deficient thymocytes, but not p38, was strengthened and prolonged in response to TCR-stimulation. All these results demonstrate that Zfat critically participates in the development of DP thymocytes through regulating the activities of p38 and JNK.