title: Pathogen-specific Treg cells expand early during mycobacterium tuberculosis infection but are later eliminated in response to Interleukin-12.
abstract: Thymically derived Foxp3⁺ regulatory T (Treg) cells have a propensity to recognize self-peptide:MHC complexes, but their ability to respond to epitope-defined foreign antigens during infectious challenge has not been demonstrated. Here we show that pulmonary infection with Mycobacterium tuberculosis (Mtb), but not Listeria monocytogenes (Lm), induced robust lymph node expansion of a highly activated population of pathogen-specific Treg cells from the pre-existing pool of thymically derived Treg cells. These antigen-specific Treg cells peaked in numbers 3 weeks after infection but subsequently underwent selective elimination driven, in part, by interleukin-12-induced intrinsic expression of the Th1-cell-promoting transcription factor T-bet. Thus, the initial Mtb-induced inflammatory response promotes pathogen-specific Treg cell proliferation, but these cells are actively culled later, probably to prevent suppression during later stages of infection. These findings have important implications for the prevention and treatment of tuberculosis and other chronic diseases in which antigen-specific Treg cells restrict immunity.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Shafiani
authors.forename: Crystal
authors.initials: C
authors.lastname: Dinh
authors.forename: James M
authors.initials: JM
authors.lastname: Ertelt
authors.forename: Albanus O
authors.initials: AO
authors.lastname: Moguche
authors.forename: Imran
authors.initials: I
authors.lastname: Siddiqui
authors.forename: Kate S
authors.initials: KS
authors.lastname: Smigiel
authors.forename: Pawan
authors.initials: P
authors.lastname: Sharma
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Campbell
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Urdahl
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017637:Clonal Deletion; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057131:Immune Evasion; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology*; D013950:Thymus Gland / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D010446:Peptide Fragments; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12