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 3

Activated APCs induce Th22 subset expansion.

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Activated APCs induce Th22 subset expansion. (A) Monocytes (MOs), Mϕ, an...
(A) Monocytes (MOs), Mϕ, and DCs were left untreated or stimulated with Pam3CysSK4, LPS, poly (I:C), or CpG oligodeoxynucleotides (ODNs) for 18 hours. Cytokine production was determined by ELISA. (B–D) Monocytes, Mϕ, or DCs were left untreated or stimulated with LPS for 5 hours and then cultured for 8 days with autologous T cells, naive T cells, or memory T cells as described in Methods. Proliferation (Ki67) and expression of IFN-γ and IL-17 in Th22 cells were detected by FACS. Numbers in quadrants indicate the percentage of cells in each quadrant. (E) Blockade of TNF-α, IL-1β, IL-6, IL-23, and/or TGF-β changed the subset composition of Th22 cells expanded by LPS-stimulated monocytes. (F and G) T cells were left untreated or cultured with conditioned media from LPS- or Pam3CysSK4-stimulated monocytes, Mϕ, or DCs for 7 days (F) or for the indicated times (G), as described in Methods. Activation of STAT proteins was detected by immunoblotting. IL-4–treated T cells served as a positive control. (H) Inhibiting STAT1 and STAT3 activation changed the subset composition of Th22 cells expanded by LPS-stimulated monocytes. Th22 subset composition was determined by FACS. Th22 subset composition is shown in C–E and H: classical Th22, white bar; Th22/Th1, dark gray bar; Th22/Th17, light gray bar; Th22/Th17/Th1, black bar. Data represent the mean ± SEM (A, C–E, and H). Results in all panels represent 5 separate experiments (n = 5–7). *P < 0.05 and **P < 0.01, compared with untreated cells (A) or the indicated groups.