Cutting Edge: Foxj1 Protects against Autoimmunity and Inhibits Thymocyte Egress

Abstract

Previous studies suggest that the forkhead transcription factor Foxj1 inhibits spontaneous autoimmunity in part by antagonizing NF-κB activation. To test this hypothesis, we ectopically expressed Foxj1 in the T cells of lupus-prone MRL/lpr mice by backcrossing a CD2-Foxj1 transgene against the MRL/lpr background. Strikingly, CD2-Foxj1-MRL/lpr animals showed a significant reduction in lymphadenopathy, pathogenic autoantibodies, and end-organ disease—but surprisingly, reversion of autoimmunity was not attributable to modulation of NF-κB. Instead, CD2-Foxj1 transgenic mice exhibited a peripheral T cell lymphopenia, associated with an accumulation of mature single-positive thymocytes. Transgenic thymocytes demonstrated unimpaired lymphoid organ entry in adoptive transfer studies but demonstrated impaired thymic exodus in response to CCL19, apparently independent of CCR7, S1P1, and NF-κB. These findings confirm the importance of Foxj1 in the regulation of T cell tolerance but furthermore suggest a novel and specific role for Foxj1 in regulating thymic egress.

FOXO1 Regulates L-Selectin and a Network of Human T Cell Homing Molecules Downstream of Phosphatidylinositol 3-Kinase

“…In conclusion, together with previous observations showing that another forkhead transcription factor, FoxJ1, can regulate mouse T cell egress (44), our findings open a new unanticipated chapter in the biology of this large family of molecules to regulate T cell trafficking. Indeed, we have identified a new function of FOXO1 that regulates various immune response genes and is opposed by PI3K/Akt signaling in human T cells.…”

Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma

“…Previous studies have demonstrated that abnormal expression of Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma FOXJ1 is associated with autoimmune diseases and certain inflammatory diseases (35,36). This association appears to be due to the ability of FOXJ1 to suppress T cell activity, resulting in spontaneous autoimmunity (37). In addition, FOXJ1 inhibits the humoral immune response in B cells, with FOXJ1 deficiency in B cells being associated with germinal center formation and the development of autoantibodies (38).…”

Interactions of Fox proteins with inflammatory transcription-factor pathways

“…Interactions for Foxj1 with additional transcription-factor pathways in immunity almost certainly exist as suggested by the ability of Foxj1 to prevent egress of thymocytes in an apparently NF-κB-independent mechanism [13]. Furthermore, in respiratory systems, the sex-determining region on the Y chromosome (Sry)-related high-mobility group (HMG) box transcription-factor Sry-like HMG-box gene (Sox)17 can enhance Foxj1 promoter activity [14].…”