Critical role of IL-10 in the induction of low zone tolerance to contact allergens

Abstract

MethodsMice. Mice deficient for IL-10 (IL-10 -/-mice), corresponding wild-type mice (IL-10 +/+ mice) on a C57BL/6 genetic background, genetically mast cell-deficient (MC-deficient) Kit W /Kit W-v mice, and The development and mechanisms of tolerance to allergens are poorly understood. Using the murine low zone tolerance (LZT) model, where contact hypersensitivity (CHS) is prevented by repeated topical low-dose applications of contact allergens, we show that LZT induction is IL-10 dependent. IL-10 is required for the generation of LZT effector cells, that is, CD8 + regulatory T cells. Only T cells from tolerized IL-10 +/+ mice or IL-10 -/-mice reconstituted with IL-10 during LZT induction adoptively transferred LZT to naive mice and prevented CHS, whereas T cells from IL-10 -/-mice failed to do so. The IL-10 required for normal LZT development is derived from lymph node CD4 + T cells, the only skin or lymph node cell population found to produce relevant amounts of IL-10 after tolerization. CD4 + T cells derived from IL-10 +/+ mice, but not from IL-10 -/-mice, allowed the induction of LZT in adoptively transferred T cell-deficient mice. Interestingly, IL-10 injections during tolerization greatly enhanced LZT responses in normal mice. Thus, the generation of CD8 + LZT effector T cells by CD4 + regulatory T cells via IL-10 may be a promising target of strategies aimed at preventing contact allergies and other harmful immune responses.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Repeated exposure to hair dye induces regulatory T cells in mice

“…It has been shown that ultraviolet B irradiation of the skin prior to allergen exposure, oral exposure to the allergen or skin exposure to low doses of the allergen can lead to allergen tolerance. [6][7][8] Although different mechanisms initiate the development of tolerance, they all lead to the induction of regulatory T cells (Tregs). [6][7][8] Different types of CD4+ Tregs have been described: naturally occurring CD4+CD25+Foxp3+ T cells, induced CD4+CD25+Foxp3+ T cells, and Tr1 and Th3 cells defined by prominent release of interleukin (IL)-10 and transforming growth factor (TGF)-b, respectively.…”

“…[6][7][8] Although different mechanisms initiate the development of tolerance, they all lead to the induction of regulatory T cells (Tregs). [6][7][8] Different types of CD4+ Tregs have been described: naturally occurring CD4+CD25+Foxp3+ T cells, induced CD4+CD25+Foxp3+ T cells, and Tr1 and Th3 cells defined by prominent release of interleukin (IL)-10 and transforming growth factor (TGF)-b, respectively. 9,10 All of these CD4+ Tregs are able to control the immune response to contact allergens by impeding the development and function of allergen-specific effector T cells.…”

“…9,10 All of these CD4+ Tregs are able to control the immune response to contact allergens by impeding the development and function of allergen-specific effector T cells. [6][7][8][9]11,12 This is done either by cell-cell interactions or by the release of anti-inflammatory cytokines such as IL-10 and TGF-b. Interestingly, nickel-specific Tregs that mediate tolerance to nickel in nonallergic individuals have been found.…”

Platelets are important for the development of immune tolerance: Possible involvement of TGF‐β in the mechanism

“…First, under the conditions at normal platelet counts, the ear swelling response was decreased at 24 hours after challenge in the mice with LZT than in those without LZT ( Figure S1A), as previously reported. [20][21][22] Furthermore, a histological examination revealed that the cell infiltration in the dermis was downregulated in the mice with LZT ( Figure S1B,C). In addition, the frequency of Foxp3 + Tregs among all infiltrating cells in the inflamed skin was increased in the mice with LZT ( Figure S2B).…”

“…[20][21][22] In a model of LZT, IL-10-secreting regulatory CD4 + CD25 + Foxp3 + Treg cells evoke the generation of CD8 + suppressor/regulatory T cell, which prevent the induction of the contact hypersensitivity (CHS). [20][21][22] First, we showed that the repeated epicutaneous application of low doses of contact allergens suppressed the CHS responses with a high percentage of Foxp3 + Treg cells in the inflamed skin and draining lymph nodes (LNs). Next, we examined whether platelets were associated with the immune tolerance induction of the CHS responses, with or without platelet depletion during LZT.…”