Abstract
Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. However, the function of Chi3l1 in T cell and its clinical implications are largely unknown. Here we show that Chi3l1 expression was increased in activated T cells, especially in Th2 cells. In addition, Chi3l1-deficient T cells are hyper-responsive to TcR stimulation and are prone to differentiating into Th1 cells. Chi3l1-deficient Th1 cells show increased expression of anti-tumor immunity genes and decreased Th1 negative regulators. Deletion of Chi3l1 in T cells in mice show reduced melanoma lung metastasis with increased IFNγ and TNFα-producing T cells in the lung. Furthermore, silencing of Chi3l1 expression in the lung using peptide-siRNA complex (dNP2-siChi3l1) efficiently inhibit lung metastasis with enhanced Th1 and CTL responses. Collectively, this study demonstrates Chi3l1 is a regulator of Th1 and CTL which could be a therapeutic target to enhance anti-tumor immunity.
Highlights
Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer
Chi3l1-deficient T cells were differentiated into T cells with Th1-prone phenotypes with hyper-responsive to IFNγ signaling and melanoma lung metastasis was significantly reduced in the mice with both Chi3l1 total knock out and CD4−Cre system
To investigate whether Chi3l1 is a negative regulator of T cell activation, MACS-purified naïve CD4 and FACS-purified CD8 T cells from wild type (WT) and Chi3l1 knock out (KO) mouse splenocytes were activated by anti-CD3 and antiCD28 antibodies for 3 days
Summary
Chitinase-3-like-1 (Chi3l1) is known to play a significant role in the pathogenesis of Type 2 inflammation and cancer. Chitinase-like proteins (CLPs) are evolutionarily conserved in mammals but do not have the enzymatic activity to directly degrade chitin[4,5] They have evolved to be important in the development and progression of Th2 inflammation, parasitic infections, and cancer[6,7,8,9,10,11]. Chi3l1-deficient T cells were differentiated into T cells with Th1-prone phenotypes with hyper-responsive to IFNγ signaling and melanoma lung metastasis was significantly reduced in the mice with both Chi3l1 total knock out and CD4−Cre system. These studies suggest that Chi3l1 plays an essential role in regulation of Th1 and CTL differentiation These studies highlight that specific intervention of Chi3l1 in T cells could be an effective therapy of pulmonary metastasis
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