How to wake a sleeping lymphocyte

According to new research published in Science, downregulation of the Fox (forkhead)-family transcription factor Foxj1 in the lymphoid system can make naive T helper (T_H) cells more responsive to the activating signals that wake them from their slumber.

These investigations arose from the initial observation that Foxj1 is downregulated in lymphocytes from mice that are prone to systemic lupus erythematosus. Having shown that Foxj1 is highly expressed by wild-type naive T cells but is rapidly downregulated when the cells are stimulated, the authors set out to examine the role of this factor in the regulation of immune responses. As most mice with Foxj1 mutations die in utero or soon after birth, they transplanted Foxj1^−/− fetal livers into Rag^−/− mice to generate chimeric animals with a Foxj1^−/− lymphoid system. Initial analyses showed that these mice had systemic autoimmune inflammation with lymphocytic infiltrates of various organs. B-cell responses were normal, as were T- and B-cell development, but the chimeric animals had a slightly higher percentage of peripheral CD4⁺ T cells with an activated cell-surface phenotype.

Further in vitro studies showed that the Foxj1^−/− CD4⁺ T_H cells produced higher levels of the T_H1-type cytokines interleukin-2 and interferon-γ in response to stimulation through CD3 compared with wild-type cells. This was associated with an increased ratio of the T_H1 transcription factor T-bet to the T_H2 transcription factor GATA3. However, when stimulated under the appropriate polarizing conditions, the Foxj1^−/− T cells could also produce higher levels of T_H2-type cytokines than their wild-type counterparts, indicating that Foxj1 is probably involved in repressing naive T-cell activation in general rather than in T_H-cell skewing. In support of this, deletion of Foxj1 was shown to result in the hyperproliferation of T_H cells in response to self-targets.

T-cell activation is in part controlled by the transcription factor nuclear factor-κB (NF-κB), and this study went on to show that Foxj1 is an upstream inhibitor of spontaneous and inducible NF-κB activity in cell lines. Furthermore, Foxj1^−/− T_H cells had increased spontaneous NF-κB activity, and blocking NF-κB prevented the hyper-responsiveness of these cells. The inhibitory effect of Foxj1 was probably the result of upregulation of IκBβ, which, as part of the inhibitor of NF-κB (IκB) complex, prevents the translocation of NF-κB to the nucleus.

It seems that Foxj1 maintains naive CD4⁺ T_H cells in a quiescent state by inhibiting NF-κB activity, thereby preventing inappropriate and possibly self-reactive inflammatory responses. This study adds to the known role of other Fox-family members in the immune system, such as Foxp3 in regulatory T cells, Foxo proteins in lymphocyte proliferation and apoptosis, and Foxn1 in thymic epithelial-cell development.