title: Foxp3-deficient regulatory T cells do not revert into conventional effector CD4+ T cells but constitute a unique cell subset.
abstract: Homeostasis in the immune system is maintained by specialized regulatory CD4(+) T cells (T(reg)) expressing transcription factor Foxp3. According to the current paradigm, high-affinity interactions between TCRs and class II MHC-peptide complexes in thymus "instruct" developing thymocytes to up-regulate Foxp3 and become T(reg) cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of T(reg) cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient T(reg) cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of T(reg) cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient T(reg) cells expressed a low level of activation markers, did not expand relative to other CD4(+) T cells, and produced IL-4 and immunomodulatory cytokines IL-10 and TGF-beta when stimulated. Global gene expression profiling revealed significant similarities between T(reg) cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert T(reg) cells into conventional effector CD4(+) T cells but rather these cells constitute a distinct cell subset with unique features.
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Kuczma
authors.forename: Robert
authors.initials: R
authors.lastname: Podolsky
authors.forename: Nikhil
authors.initials: N
authors.lastname: Garge
authors.forename: Danielle
authors.initials: D
authors.lastname: Daniely
authors.forename: Rafal
authors.initials: R
authors.lastname: Pacholczyk
authors.forename: Leszek
authors.initials: L
authors.lastname: Ignatowicz
authors.forename: Piotr
authors.initials: P
authors.lastname: Kraj
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D006706:Homeostasis / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D016176:T-Lymphocyte Subsets / Q000145:classification*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse