title: CD4+CD25+Foxp3+ regulatory T cells are dispensable for controlling CD8+ T cell-mediated lung inflammation.
abstract: Every person harbors a population of potentially self-reactive lymphocytes controlled by tightly balanced tolerance mechanisms. Failures in this balance evoke immune activation and autoimmunity. In this study, we investigated the contribution of self-reactive CD8(+) T lymphocytes to chronic pulmonary inflammation and a possible role for naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that despite pulmonary inflammation, lung-specific CD8(+) T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8(+) T cells in the inflamed lung and lung-draining lymph nodes downregulated the expression of effector molecules, those located in the spleen appeared to be partly Ag-experienced and displayed a memory-like phenotype. Because ex vivo-reisolated self-reactive CD8(+) T cells were very well capable of responding to the Ag in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8(+) T cells in the lung. Notably, CD8(+) T cell tolerance established in the lung depends only partially on the function of nTregs, because self-reactive CD8(+) T cells underwent only biased activation and did not acquire effector function after nTreg depletion. However, although transient ablation of nTregs did not expand the population of self-reactive CD8(+) T cells or exacerbate the disease, it provoked rapid accumulation of activated CD103(+)CD62L(lo) Tregs in bronchial lymph nodes, a finding suggesting an adaptive phenotypic switch in the nTreg population that acts in concert with other yet-undefined mechanisms to prevent the detrimental activation of self-reactive CD8(+) T cells.
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
authors.forename: Milena J
authors.initials: MJ
authors.lastname: Tosiek
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Bader
authors.forename: Susanne
authors.initials: S
authors.lastname: Mauel
authors.forename: Heinz-Gerd
authors.initials: HG
authors.lastname: Hoymann
authors.forename: Silvia
authors.initials: S
authors.lastname: Prettin
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Marcus
authors.initials: M
authors.lastname: Gereke
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020869:Gene Expression Profiling; D007108:Immune Tolerance / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012129:Respiratory Function Tests; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; D053645:Interleukin-2 Receptor alpha Subunit; C091367:alpha E integrins; D019041:L-Selectin