B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets
Dong-Ming Kuang, … , Hong Deng, Limin Zheng
Dong-Ming Kuang, … , Hong Deng, Limin Zheng
Published September 17, 2014
Citation Information: J Clin Invest. 2014;124(10):4657-4667. https://doi.org/10.1172/JCI74381.
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Research Article Oncology

B7-H1–expressing antigen-presenting cells mediate polarization of protumorigenic Th22 subsets

Abstract

Classical IL-22–producing T helper cells (Th22 cells) mediate inflammatory responses independently of IFN-γ and IL-17; however, nonclassical Th22 cells have been recently identified and coexpress IFN-γ and/or IL-17 along with IL-22. Little is known about how classical and nonclassical Th22 subsets in human diseases are regulated. Here, we used samples of human blood, normal and peritumoral liver, and hepatocellular carcinoma (HCC) to delineate the phenotype, distribution, generation, and functional relevance of various Th22 subsets. Three nonclassical Th22 subsets constituted the majority of all Th22 cells in human liver and HCC tissues, although the classical Th22 subset was predominant in blood. Monocytes activated by TLR2 and TLR4 agonists served as the antigen-presenting cells (APCs) that most efficiently triggered the expansion of nonclassical Th22 subsets from memory T cells and classical Th22 subsets from naive T cells. Moreover, B7-H1–expressing monocytes skewed Th22 polarization away from IFN-γ and toward IL-17 through interaction with programmed death 1 (PD-1), an effect that can create favorable conditions for in vivo aggressive cancer growth and angiogenesis. Our results provide insight into the selective modulation of Th22 subsets and suggest that strategies to influence functional activities of inflammatory cells may benefit anticancer therapy.

Authors

Dong-Ming Kuang, Xiao Xiao, Qiyi Zhao, Min-Min Chen, Xue-Feng Li, Rui-Xian Liu, Yuan Wei, Fang-Zhu Ouyang, Dong-Ping Chen, Yan Wu, Xiang-Ming Lao, Hong Deng, Limin Zheng

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Figure 4

Monocyte B7-H1 regulates the balance between IFN-γ– and IL-17–related Th22 cells.

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Monocyte B7-H1 regulates the balance between IFN-γ– and IL-17–related Th...
(A) Real-time PCR determination of relative fold changes in the indicated cytokine mRNAs in monocytes from paired samples of blood and peritumoral liver and tumor tissues from 11 HCC patients. (B) FACS analysis of expression of the indicated markers on monocytes from paired samples of blood and peritumoral liver and tumor tissues from 4 HCC patients. (C and D) Purified T cells were cultured for 8 days with autologous peritumoral liver or tumor monocytes (C) or LPS-stimulated peripheral monocytes (D) in the presence of an anti–B7-H1 or a control Ab, as described in Methods. Expression of IL-22 in Th cells and expression of IFN-γ and IL-17 in Th22 are shown. Numbers in quadrants indicate the percentage of cells in each quadrant. (E and F) T cells were left untreated or were cultured with mock, B7-H1, or B7-DC transfectant in the presence of IL-1β, IL-6, IL-23, and TGF-β for 9 days as described in Methods. In parallel, B7-H1–expressing transfectants were preincubated for 1 hour with an anti–B7-H1 or a control Ab. STAT activation on day 1 (E) and Th22 subset composition on day 8 (F) in T cells were determined by immunoblotting and FACS, respectively. Th22 subset composition is shown in F: classical Th22, white bar; Th22/Th1, dark gray bar; Th22/Th17, light gray bar; Th22/Th17/Th1, black bar. Data represent the mean ± SEM (B and F). Results represent 4 separate experiments (n = 4–6; C–F). *P < 0.05; **P < 0.01.