Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals

Xuguang Tai; Batu Erman; Amala Alag; Jie Mu; Motoko Kimura; Gil Katz; Terry Guinter; Tom McCaughtry; Ruth Etzensperger; Lionel Feigenbaum; Dinah S Singer; Alfred Singer

doi:10.1016/j.immuni.2013.02.022

Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals

Immunity. 2013 Jun 27;38(6):1116-28. doi: 10.1016/j.immuni.2013.02.022. Epub 2013 Jun 6.

Authors

Xuguang Tai¹, Batu Erman, Amala Alag, Jie Mu, Motoko Kimura, Gil Katz, Terry Guinter, Tom McCaughtry, Ruth Etzensperger, Lionel Feigenbaum, Dinah S Singer, Alfred Singer

Affiliation

¹ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract

Immune tolerance requires regulatory T (Treg) cells to prevent autoimmune disease, with the transcription factor Foxp3 functioning as the critical regulator of Treg cell development and function. We report here that Foxp3 was lethal to developing Treg cells in the thymus because it induced a unique proapoptotic protein signature (Puma⁺⁺⁺p-Bim⁺⁺p-JNK⁺⁺DUSP6⁻) and repressed expression of prosurvival Bcl-2 molecules. However, Foxp3 lethality was prevented by common gamma chain (γc)-dependent cytokine signals that were present in the thymus in limiting amounts sufficient to support only ∼1 million Treg cells. Consequently, most newly arising Treg cells in the thymus were deprived of this signal and underwent Foxp3-induced death, with Foxp3⁺CD25⁻ Treg precursor cells being the most susceptible. Thus, we identify Foxp3 as a proapoptotic protein that requires developing Treg cells to compete with one another for limiting amounts of γc-dependent survival signals in the thymus.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Animals
Apoptosis / genetics
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Bcl-2-Like Protein 11
Cell Survival
Cells, Cultured
Cytokines / immunology*
Dual Specificity Phosphatase 6 / genetics
Dual Specificity Phosphatase 6 / metabolism
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation, Developmental
Interleukin Receptor Common gamma Subunit / immunology*
Lymphopoiesis / genetics
MAP Kinase Kinase 4 / genetics
MAP Kinase Kinase 4 / metabolism
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Knockout
Mice, Transgenic
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
T-Lymphocytes, Regulatory / physiology*
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Bcl2l11 protein, mouse
Cytokines
Forkhead Transcription Factors
Foxp3 protein, mouse
Interleukin Receptor Common gamma Subunit
Membrane Proteins
PUMA protein, mouse
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
Tumor Suppressor Proteins
MAP Kinase Kinase 4
Dual Specificity Phosphatase 6
Dusp6 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding