Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus.
Regulatory T cells (Tregs) differentiate in the thymus, but the mechanisms that control this process are not fully understood. We generated a comprehensive quantitative and differential proteome of murine Tregs and conventional T cells. We identified 5225 proteins, 164 of which were differentially expressed in Tregs. Together with the comparative analysis of proteome and gene expression data, we identified TCF7 as a promising candidate. Genetic elimination of transcription factor 7 (TCF7) led to increased fractions of Tregs in the thymus. Reduced levels of TCF7, found in the heterozygote, resulted in a greater potential for Treg precursors to differentiate into the Treg lineage. In contrast, activation of TCF7 through β-catenin had the opposite effect. TCF7 levels influenced the required TCR signaling strength of Treg precursors, and TCF7 deficiency broadened the repertoire and allowed lower TCR affinities to be recruited into the Treg lineage. FOXP3 was able to repress TCF7 protein expression. In summary, we propose a regulatory role for TCF7 in limiting access to the Treg lineage.
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
Melanie M
MM
Barra
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
David M
DM
Richards
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Jenny
J
Hansson
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
Ann-Cathrin
AC
Hofer
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
Michael
M
Delacher
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and.
Jan
J
Hettinger
Genome Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Jeroen
J
Krijgsveld
Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany; and m.feuerer@dkfz-heidelberg.de.
Markus
M
Feuerer
D000818:Animals; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020543:Proteome / Q000032:analysis; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D051176:beta Catenin / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D020543:Proteome; D051176:beta Catenin