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Foxp3  -  forkhead box P3

Mus musculus

Synonyms: Forkhead box protein P3, JM2, Scurfin, scurfin, sf
 
 
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Disease relevance of Foxp3

  • PSI-APC Treg cells expressed high levels of Foxp3, inhibited proliferation of naive DO11.10 T cells in vivo, and abrogated colitis driven by a memory Th1 response to bacterial-associated Ag [1].
  • Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization [2].
  • Scurfy mice, which are deficient in a functional Foxp3, exhibit a severe lymphoproliferative disorder and display generalized over-production of cytokines [3].
  • In adult day 3-thymectomized mice, the CD25(+)CD4(+) T cell subset is overrepresented (most of the cells being CD103(+)) and expresses high amounts of Foxp3 mRNA, independent of the development of autoimmune gastritis [4].
  • Finally, we show that myelin proteolipid protein-specific autoreactive T cells transduced with Foxp3 cannot mediate experimental autoimmune encephalomyelitis, providing further support that Foxp3 suppresses the effector function of autoreactive T cells [3].
 

High impact information on Foxp3

  • Lack of Foxp3 leads to development of fatal autoimmune lymphoproliferative disease; furthermore, ectopic Foxp3 expression can phenotypically convert effector T cells to regulatory T cells [5].
  • Genetic complementation demonstrates that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis [6].
  • Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse [6].
  • Development of CD8(+) T cells and NKT cells, maintenance of peripheral Foxp3-expressing regulatory T cells, and survival of CD4(+) T cells all depended on TGF-beta signaling [7].
  • We show that expression of Foxp3 is highly restricted to the subset alphabeta of T cells and, irrespective of CD25 expression, correlates with suppressor activity [8].
 

Chemical compound and disease context of Foxp3

  • Taken together, our results provide insight into the mechanism that controls autoimmune diseases via the deletion of this single glutamic acid residue in the leucine-zipper domain of Foxp3 [9].
  • For testing the in vivo significance of this effect, CD4(+)CD25(+) T cells that expressed high levels of Foxp3 were reconstituted into SCID mice after induction of Adriamycin nephropathy, a noncognate model of chronic renal disease [10].
 

Biological context of Foxp3

 

Anatomical context of Foxp3

  • CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2 [12].
  • In this study, we show that CD4+CD25+ T reg cells that expressed Foxp3 transcription factor were nearly absent in both thymus and peripheral lymphoid organs of LAT(Y136F) mice [16].
  • Using this mouse model, we assessed Foxp3 expression in various lymphocyte compartments and identified previously unreported Foxp3-expressing cells [17].
  • Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells [3].
  • Interestingly, also development of a small subpopulation of CD25-expressing T cells lacking expression of the transcription factor Foxp3, thought to be autospecific, is enhanced by expression of the agonist ligand on thymic epithelium [18].
 

Associations of Foxp3 with chemical compounds

 

Regulatory relationships of Foxp3

  • By quantitative reverse transcription-PCR, we show that the CD25+ population is highly enriched in mRNA for the Foxp3 transcription factor and that these cells express significantly more IL-10 mRNA than the CD25- population, suggesting a likely regulatory phenotype [23].
  • TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential [24].
  • We also demonstrate that regulation of both Th1- and Th2-type cytokine secretion in CD4 T cells that express wild-type Foxp3 is significantly altered by the deletion of glutamic acid [9].
  • Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin [25].
  • Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection [26].
  • We identify a population of CD103(+) mesenteric lymph node dendritic cells (DCs) that induce the development of Foxp3(+) T reg cells [27].
 

Other interactions of Foxp3

  • A function for interleukin 2 in Foxp3-expressing regulatory T cells [13].
  • In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice [13].
  • Analysis of tumor-infiltrating T lymphocyte populations showed that the expression of Foxp3 and IL-10 was associated with CD4(+)CD25(+) T cells [28].
  • Nevertheless, CD28 costimulation provides more than interleukin 2 to developing T(reg) cells, as CD28 costimulation of T cell receptor-signaled double-positive thymocytes induced expression of Foxp3, considered to be the T(reg) 'master gene', as well as GITR and CTLA-4, two proteins expressed on T(reg) cells [12].
  • Here we have analyzed the effects of interleukin 2 or CD25 deficiency on agonist-driven thymic development and the peripheral homeostasis of an antigen-specific population of regulatory T cells positive for forkhead family transcription factor Foxp3 and have correlated our observations with polyclonal suppressor populations [29].
 

Analytical, diagnostic and therapeutic context of Foxp3

References

  1. Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function. Cong, Y., Konrad, A., Iqbal, N., Hatton, R.D., Weaver, C.T., Elson, C.O. J. Immunol. (2005) [Pubmed]
  2. Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. Setoguchi, R., Hori, S., Takahashi, T., Sakaguchi, S. J. Exp. Med. (2005) [Pubmed]
  3. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Bettelli, E., Dastrange, M., Oukka, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Regulatory potential and control of Foxp3 expression in newborn CD4+ T cells. Dujardin, H.C., Burlen-Defranoux, O., Boucontet, L., Vieira, P., Cumano, A., Bandeira, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. FOXP3: Of Mice and Men. Ziegler, S.F. Annu. Rev. Immunol. (2006) [Pubmed]
  6. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Brunkow, M.E., Jeffery, E.W., Hjerrild, K.A., Paeper, B., Clark, L.B., Yasayko, S.A., Wilkinson, J.E., Galas, D., Ziegler, S.F., Ramsdell, F. Nat. Genet. (2001) [Pubmed]
  7. Transforming Growth Factor-beta Controls Development, Homeostasis, and Tolerance of T Cells by Regulatory T Cell-Dependent and -Independent Mechanisms. Li, M.O., Sanjabi, S., Flavell, R.A. Immunity (2006) [Pubmed]
  8. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Fontenot, J.D., Rasmussen, J.P., Williams, L.M., Dooley, J.L., Farr, A.G., Rudensky, A.Y. Immunity (2005) [Pubmed]
  9. The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Chae, W.J., Henegariu, O., Lee, S.K., Bothwell, A.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. CD4+CD25+ Regulatory T Cells Protect against Injury in an Innate Murine Model of Chronic Kidney Disease. Mahajan, D., Wang, Y., Qin, X., Wang, Y., Zheng, G., Wang, Y.M., Alexander, S.I., Harris, D.C. J. Am. Soc. Nephrol. (2006) [Pubmed]
  11. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Khattri, R., Cox, T., Yasayko, S.A., Ramsdell, F. Nat. Immunol. (2003) [Pubmed]
  12. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Tai, X., Cowan, M., Feigenbaum, L., Singer, A. Nat. Immunol. (2005) [Pubmed]
  13. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Fontenot, J.D., Rasmussen, J.P., Gavin, M.A., Rudensky, A.Y. Nat. Immunol. (2005) [Pubmed]
  14. Impaired regulatory T cell function in germ-free mice. Ostman, S., Rask, C., Wold, A.E., Hultkrantz, S., Telemo, E. Eur. J. Immunol. (2006) [Pubmed]
  15. Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice. Luo, X., Yang, H., Kim, I.S., Saint-Hilaire, F., Thomas, D.A., De, B.P., Ozkaynak, E., Muthukumar, T., Hancock, W.W., Crystal, R.G., Suthanthiran, M. Transplantation (2005) [Pubmed]
  16. LAT-mediated signaling in CD4+CD25+ regulatory T cell development. Koonpaew, S., Shen, S., Flowers, L., Zhang, W. J. Exp. Med. (2006) [Pubmed]
  17. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Wan, Y.Y., Flavell, R.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  18. Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR repertoire. Ribot, J., Romagnoli, P., van Meerwijk, J.P. J. Immunol. (2006) [Pubmed]
  19. Induction of CD4+CD25+ regulatory T cells by copolymer-I through activation of transcription factor Foxp3. Hong, J., Li, N., Zhang, X., Zheng, B., Zhang, J.Z. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  20. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. Fallarino, F., Grohmann, U., You, S., McGrath, B.C., Cavener, D.R., Vacca, C., Orabona, C., Bianchi, R., Belladonna, M.L., Volpi, C., Santamaria, P., Fioretti, M.C., Puccetti, P. J. Immunol. (2006) [Pubmed]
  21. Neuroimmunoprotective effects of estrogen and derivatives in experimental autoimmune encephalomyelitis: therapeutic implications for multiple sclerosis. Offner, H. J. Neurosci. Res. (2004) [Pubmed]
  22. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Sharma, S., Yang, S.C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M., Batra, R.K., Dubinett, S.M. Cancer Res. (2005) [Pubmed]
  23. Regulatory T cells modulate Th2 responses induced by Brugia pahangi third-stage larvae. Gillan, V., Devaney, E. Infect. Immun. (2005) [Pubmed]
  24. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. Chen, W., Jin, W., Hardegen, N., Lei, K.J., Li, L., Marinos, N., McGrady, G., Wahl, S.M. J. Exp. Med. (2003) [Pubmed]
  25. Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance. Muthukumarana, P.A., Lyons, G.E., Miura, Y., Thompson, L.H., Watson, T., Green, C.J., Shurey, S., Hess, A.D., Rosengard, B.R., Metcalfe, S.M. Int. Immunopharmacol. (2006) [Pubmed]
  26. Foxp3 controls autoreactive T cell activation through transcriptional regulation of early growth response genes and E3 ubiquitin ligase genes, independently of thymic selection. Chang, X., Chen, L., Wen, J., Godfrey, V.L., Qiao, G., Hussien, Y., Zhang, J., Gao, J.X. Clin. Immunol. (2006) [Pubmed]
  27. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. Coombes, J.L., Siddiqui, K.R., Arancibia-Cárcamo, C.V., Hall, J., Sun, C.M., Belkaid, Y., Powrie, F. J. Exp. Med. (2007) [Pubmed]
  28. Chronic immune therapy induces a progressive increase in intratumoral T suppressor activity and a concurrent loss of tumor-specific CD8+ T effectors in her-2/neu transgenic mice bearing advanced spontaneous tumors. Nair, R.E., Kilinc, M.O., Jones, S.A., Egilmez, N.K. J. Immunol. (2006) [Pubmed]
  29. Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. D'Cruz, L.M., Klein, L. Nat. Immunol. (2005) [Pubmed]
  30. Dynamics of CD4+CD25+ T Cells in Spleens and Mesenteric Lymph Nodes of Mice Infected with Schistosoma japonicum. Cai, X.P., Zhang, H., Zhang, Y.C., Wang, Y., Su, C., Ji, M.J., Wu, H.W., Zhu, X., Zhang, Z.S., Wu, G.L. Acta Biochim. Biophys. Sin. (Shanghai) (2006) [Pubmed]
  31. Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. Lee, I., Wang, L., Wells, A.D., Dorf, M.E., Ozkaynak, E., Hancock, W.W. J. Exp. Med. (2005) [Pubmed]
  32. Heme Oxygenase-1-Mediated CD4+CD25high Regulatory T Cells Suppress Allergic Airway Inflammation. Xia, Z.W., Zhong, W.W., Xu, L.Q., Sun, J.L., Shen, Q.X., Wang, J.G., Shao, J., Li, Y.Z., Yu, S.C. J. Immunol. (2006) [Pubmed]
  33. Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice. Lin, W., Truong, N., Grossman, W.J., Haribhai, D., Williams, C.B., Wang, J., Martín, M.G., Chatila, T.A. J. Allergy Clin. Immunol. (2005) [Pubmed]
 
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