Regulatory T Cell Numbers in Inflamed Skin Are Controlled by Local Inflammatory Cues That Upregulate CD25 and Facilitate Antigen-Driven Local Proliferation

J Immunol. 2016 Sep 15;197(6):2208-18. doi: 10.4049/jimmunol.1502575. Epub 2016 Aug 10.


CD4(+)Foxp3(+) regulatory T cells (Tregs) are key immune suppressors that regulate immunity in diverse tissues. The tissue and/or inflammatory signals that influence the magnitude of the Treg response remain unclear. To define signals that promote Treg accumulation, we developed a simple system of skin inflammation using defined Ags and adjuvants that induce distinct cytokine milieus: OVA protein in CFA, aluminum salts (Alum), and Schistosoma mansoni eggs (Sm Egg). Polyclonal and Ag-specific Treg accumulation in the skin differed significantly between adjuvants. CFA and Alum led to robust Treg accumulation, with >50% of all skin CD4(+) T cells being Foxp3(+) In contrast, Tregs accumulated poorly in the Sm Egg-inflamed skin. Surprisingly, we found no evidence of inflammation-specific changes to the Treg gene program between adjuvant-inflamed skin types, suggesting a lack of selective recruitment or adaptation to the inflammatory milieu. Instead, Treg accumulation patterns were linked to differences in CD80/CD86 expression by APC and the regulation of CD25 expression, specifically in the inflamed skin. Inflammatory cues alone, without cognate Ag, differentially supported CD25 upregulation (CFA and Alum > Sm Egg). Only in inflammatory milieus that upregulated CD25 did the provision of Ag enhance local Treg proliferation. Reduced IL-33 in the Sm Egg-inflamed environment was shown to contribute to the failure to upregulate CD25. Thus, the magnitude of the Treg response in inflamed tissues is controlled at two interdependent levels: inflammatory signals that support the upregulation of the important Treg survival factor CD25 and Ag signals that drive local expansion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens / immunology
  • B7-1 Antigen / analysis
  • B7-2 Antigen / analysis
  • Dermatitis / immunology*
  • Female
  • Inflammation / immunology
  • Interferon-gamma / biosynthesis
  • Interleukin-2 Receptor alpha Subunit / physiology*
  • Interleukin-4 / biosynthesis
  • Lymphocyte Activation*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred BALB C
  • Skin / immunology*
  • T-Lymphocytes, Regulatory / immunology*


  • Antigens
  • B7-1 Antigen
  • B7-2 Antigen
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-4
  • Interferon-gamma