title: Naturally occurring regulatory T cells: markers, mechanisms, and manipulation.
abstract: Naturally occurring CD4(+)CD25(high) forkhead box protein 3 (FOXP3)(+) regulatory T cells (nTregs) are key mediators of immunity, which orchestrate and maintain tolerance to self and foreign antigens. In the recent 1.5 decades, a multitude of studies have aimed to define the phenotype and function of nTregs and to assess their therapeutic potential for modulating immune mediated disorders such as autoimmunity, allergy, and episodes of transplant rejection. In this review, we summarize the current knowledge on the biology of nTregs. We address the exact definition of nTregs by specific markers and combinations thereof, which is a prerequisite for the state-of-the-art isolation of defined nTreg populations. Furthermore, we discuss the mechanism by which nTregs mediate immunosuppression and how this knowledge might translate into novel therapeutic modalities. With first clinical studies of nTreg-based therapies being finished, questions concerning the reliable sources of nTregs are becoming more and more eminent. Consequently, approaches allowing conversion of CD4(+) T cells into nTregs by coculture with antigen-presenting cells, cytokines, and/or pharmacological agents are discussed. In addition, genetic engineering approaches for the generation of antigen-specific nTregs are described.
authors.affiliation: Institute of Immunology, Center for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Borschkegasse 8A, A-1090 Vienna, Austria.
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Schmetterer
authors.forename: Alina
authors.initials: A
authors.lastname: Neunkirchner
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D015703:Antigens, CD / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D037161:Galectins / Q000378:metabolism; D005818:Genetic Engineering; D053804:Granzymes / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D039001:Integrin alpha Chains / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D054353:Perforin / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C497483:CD44 protein, human; D060908:CTLA-4 Antigen; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037161:Galectins; D018960:Hyaluronan Receptors; C111431:IKZF2 protein, human; C508609:IL10 protein, human; C508017:IL2RA protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D039001:Integrin alpha Chains; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; C091367:alpha E integrins; C523496:galectin 10, human; D054353:Perforin; D016753:Interleukin-10; D051740:Ikaros Transcription Factor; D053804:Granzymes