Skin inflammation arising from cutaneous regulatory T cell deficiency leads to impaired viral immune responses

Eva Jasmin Freyschmidt, Clinton B. Mathias, Natalia Diaz, Daniel H. MacArthur, Amale Laouar, Narasimhaswamy Manjunath, Matthias D. Hofer, Marc Andre Wurbel, James J. Campbell, Talal A. Chatila, Hans C. Oettgen

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21 Scopus citations

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 (FoxP3KO) mice, which completely lack FoxP3+ Treg. These animals generated both fewer VV-specific. CD8 + effector T cells and IFN-γ-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 CCR4KO FoxP3KO bone marrow (CCR4/FoxP3) chimeras in which skin, but not other tissues or central lymphoid organs, lack Treg. Like FoxP3KO 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-β, 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.

Original languageEnglish (US)
Pages (from-to)1295-1302
Number of pages8
JournalJournal of Immunology
Volume185
Issue number2
DOIs
StatePublished - Jul 15 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Freyschmidt, E. J., Mathias, C. B., Diaz, N., MacArthur, D. H., Laouar, A., Manjunath, N., Hofer, M. D., Wurbel, M. A., Campbell, J. J., Chatila, T. A., & Oettgen, H. C. (2010). Skin inflammation arising from cutaneous regulatory T cell deficiency leads to impaired viral immune responses. Journal of Immunology, 185(2), 1295-1302. https://doi.org/10.4049/jimmunol.0903144