IL-22-Expressing Murine Lymphocytes Display Plasticity and Pathogenicity in Reporter Mice.

Wei Shen,Mairi H Mclean,Julie A Hixon,Scott K Durum,Wen Qing Li

doi:10.3389/fimmu.2015.00662

Wei Shen, Mairi H Mclean + Show 3 more

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https://doi.org/10.3389/fimmu.2015.00662

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Abstract

IL-22 has multiple activities ranging from tissue repair to inflammation. To characterize the pathogenicity and plasticity of cells that produce IL-22, a novel reporter mouse strain was generated. Homeostatic IL-22 reporter expression was observed in intestinal lymphoid cells identified as CD4 T cells and ILC3 cells. In a model of inflammatory bowel disease, CD4 T cells strongly expressed the IL-22 reporter in mesenteric lymph node. To examine plasticity of IL-22+ T cells, they were purified after generation in vitro or in vivo from inflamed colon, and then cultured under Th1, Th2, or Th17 conditions. In vitro-generated IL-22+ CD4 T cells showed relatively durable IL-22 expression under Th1 or Th2 conditions, whereas in vivo-generated cells rapidly lost IL-22 expression under these conditions. In vitro-generated cells could not be diverted to express Th1 or Th2 cytokines despite the expression of “master regulators.” In vivo-generated cells could be diverted, at very low frequency, to express Th1 or Th2 cytokines. Both in vitro- and in vivo-generated cells could be induced in vitro to express high levels of IL-17A and IL-17F, assigning them to a “Th17 biased” class. However, IL-27 potently downregulated IL-22 expression. To examine IL-22+ T cell pathogenicity, in vitro-generated cells were transferred into Rag1−/− mice, retaining the modest reporter expression and inducing moderate colitis. In contrast, IL-22 expressers from colitic mice, transferred into secondary hosts, lost reporter expression, acquired high T-bet and modest IFNγ and IL-17 expression, and induced severe colitis. These findings are consistent with a model of strong polarization under optimal in vitro conditions, but a plastic state of T cells in vivo.

Highlights

IL-22 was initially discovered as an IL-9- or activation-induced transcript in T cells [1]
Reporter expression was induced in CD4 T cells by the same combination of stimuli as the IL-22 gene (Figure 1A), and there was a similar quantitative expression of reporter transcripts compared to the endogenous IL-22 gene measured by quantitative RT-PCR
IL-22 reporter expression was prominent in the gut-associated lymphoid tissue (GALT) in innate lymphocyte (ILC) and CD4T cells

Summary

Introduction

IL-22 was initially discovered as an IL-9- or activation-induced transcript in T cells [1]. IL-22 performs important roles in host defense through its action on epithelial cells eliciting innate immune reactions [reviewed in Ref. [2]], a human subset designated “Th22” has been distinguished from Th17 cells and is a major IL-22 producer [8, 9]. This pattern in humans differs from the mouse, in which Th17 cells were reported to be major producers [7, 10]. Th1 cells were shown to be capable of expressing IL-22 [11]

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