title: Skin inflammation arising from cutaneous regulatory T cell deficiency leads to impaired viral immune responses.
abstract: Individuals with atopic dermatitis immunized with the small pox vaccine, vaccinia virus (VV), are susceptible to eczema vaccinatum (EV), a potentially fatal disseminated infection. Dysfunction of Forkhead box P3 (FoxP3)-positive regulatory T cells (Treg) has been implicated in the pathogenesis of atopic dermatitis. To test whether Treg deficiency predisposes to EV, we percutaneously VV infected FoxP3-deficient (FoxP3(KO)) mice, which completely lack FoxP3(+) Treg. These animals generated both fewer VV-specific CD8(+) effector T cells and IFN-gamma-producing CD8(+) T cells than controls, had higher viral loads, and exhibited abnormal Th2-polarized responses to the virus. To focus on the consequences of Treg deficiency confined to the skin, we generated mixed CCR4(KO) FoxP3(KO) bone marrow (CCR4/FoxP3) chimeras in which skin, but not other tissues or central lymphoid organs, lack Treg. Like FoxP3(KO) mice, the chimeras had impaired VV-specific effector T cell responses and higher viral loads. Skin cytokine expression was significantly altered in infected chimeras compared with controls. Levels of the antiviral cytokines, type I and II IFNs and IL-12, were reduced, whereas expression of the proinflammatory cytokines, IL-6, IL-10, TGF-beta, and IL-23, was increased. Importantly, infection of CCR4/FoxP3 chimeras by a noncutaneous route (i.p.) induced immune responses comparable to controls. Our findings implicate allergic skin inflammation resulting from local Treg deficiency in the pathogenesis of EV.
authors.affiliation: Division of Immunology, Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eva-Jasmin
authors.initials: EJ
authors.lastname: Freyschmidt
authors.forename: Clinton B
authors.initials: CB
authors.lastname: Mathias
authors.forename: Natalia
authors.initials: N
authors.lastname: Diaz
authors.forename: Daniel H
authors.initials: DH
authors.lastname: MacArthur
authors.forename: Amale
authors.initials: A
authors.lastname: Laouar
authors.forename: Narasimhaswamy
authors.initials: N
authors.lastname: Manjunath
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Hofer
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Wurbel
authors.forename: James J
authors.initials: JJ
authors.lastname: Campbell
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
authors.forename: Hans C
authors.initials: HC
authors.lastname: Oettgen
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D003876:Dermatitis, Atopic / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D016679:Genome, Viral / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007617:Kaposi Varicelliform Eruption / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D054398:Receptors, CCR4 / Q000235:genetics / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000473:pathology / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera / Q000097:blood / Q000276:immunology; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
chemical_list: C515355:Ccr4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D054398:Receptors, CCR4; C064658:RAG-1 protein; D007371:Interferon-gamma