title: Distinct modes of antigen presentation promote the formation, differentiation, and activity of foxp3+ regulatory T cells in vivo.
abstract: How the formation and activity of CD4(+)Foxp3(+) regulatory T cells (Tregs) are shaped by TCR recognition of the diverse array of peptide:MHC complexes that can be generated from self-antigens and/or foreign Ags in vivo remains poorly understood. We show that a self-peptide with low (but not high) stimulatory potency promotes thymic Treg formation and can induce conventional CD4(+) T cells in the periphery to become Tregs that express different levels of the transcription factor Helios according to anatomical location. When Tregs generated in response to this self-peptide subsequently encountered the same peptide derived instead from influenza virus in the lung-draining lymph nodes of infected mice, they proliferated, acquired a T-bet(+)CXCR3(+) phenotype, and suppressed the antiviral effector T cell response in the lungs. However, these self-antigen-selected Tregs were unable to suppress the antiviral immune response based on recognition of the peptide as a self-antigen rather than a viral Ag. Notably, when expressed in a more immunostimulatory form, the self-peptide inhibited the formation of T-bet(+)CXCR3(+) Tregs in response to viral Ag, and Ag-expressing B cells from these mice induced Treg division without upregulation of CXCR3. These studies show that a weakly immunostimulatory self-peptide can induce thymic and peripheral Foxp3(+) Treg formation but is unable to activate self-antigen-selected Tregs to modulate an antiviral immune response. Moreover, a strongly immunostimulatory self-peptide expressed by B cells induced Tregs to proliferate without acquiring an effector phenotype that allows trafficking from the draining lymph node to the lungs and, thereby, prevented the Tregs from suppressing the antiviral immune response.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Weissler
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Victoria
authors.initials: V
authors.lastname: Garcia
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kropf
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Malinda
authors.initials: M
authors.lastname: Aitken
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Felipe
authors.initials: F
authors.lastname: Bedoya
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Amaya I
authors.initials: AI
authors.lastname: Wolf
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104.
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104 caton@wistar.org.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D000098815:T-bet Transcription Factor
chemical_list: D000956:Antigens, Viral; D001324:Autoantigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor