IL-17–producing γδ T cells protect against Clostridium difficile infection
Yee-Shiuan Chen, … , Sing Sing Way, David B. Haslam
Yee-Shiuan Chen, … , Sing Sing Way, David B. Haslam
Published January 28, 2020
Citation Information: J Clin Invest. 2020;130(5):2377-2390. https://doi.org/10.1172/JCI127242.
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Research Article Immunology Infectious disease

IL-17–producing γδ T cells protect against Clostridium difficile infection

Abstract

Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile–induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt+ γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17–producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.

Authors

Yee-Shiuan Chen, Iuan-Bor Chen, Giang Pham, Tzu-Yu Shao, Hansraj Bangar, Sing Sing Way, David B. Haslam

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Figure 7

IL-17 and γδ T cells are more abundant in newborn mice and essential for enhanced protection against C. difficile infection compared with adult mice.

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IL-17 and γδ T cells are more abundant in newborn mice and essential for...
(A) Survival (percentage) of WT C57BL/6 adult and neonatal mice infected with various CFU of C. difficile. (B) αβ T cells and γδ T cells from uninfected adult and neonatal mice were analyzed by flow cytometry. Gating was done on live CD45+CD3ε+ TCRβ+ cells or live CD45+CD3ε+ TCRγδ+ cells. n = 4 per group. (C) RORγt expression in αβ T cells and γδ T cells from uninfected adult and neonatal mice were analyzed by flow cytometry. Gating was done on live CD45+CD3ε+ TCRβ+ cells or live CD45+CD3ε+ TCRγδ+ cells. Results are representative of 2 experiments. (D) Single-cell suspensions from intestines from adult and neonatal day-2–infected mice (1 × 106 CFU) were stimulated with PMA and ionomycin in vitro, followed by intracellular staining and flow cytometric analysis. Gating was done on live CD45+CD3ε+ TCRγδ+ IL-17A+ cells. n = 4–6 per group. (E) Survival (percentage) of neonatal WT, Il17a–/–, and Tcrd–/– mice following C. difficile infection (1 × 106 CFU; WT vs. Il17a–/– and WT vs. Tcrd–/–; P < 0.0001, by log-rank test). (F) Survival (percentage) of WT neonatal littermate mice treated with isotype control (MOPC-21 or Armenian hamster IgG), anti–IL-17A (17F3), anti-TCRγδ (UC7-13D5), or anti-TCRαβ (H57-597) after C. difficile infection (1 × 106 CFU). P < 0.05, by log-rank test. Neonatal mice received 100 μg antibody on day –2, followed by a second dose on day 0. (G) Survival (percentage) of WT neonatal littermate mice treated with isotype controls (MOPC-21 and Armenian hamster IgG), anti–IL-17A (17F3), or anti-TCRγδ (UC7-13D5) plus anti–IL-17A following C. difficile infection (1 × 106 CFU. Anti–IL-17A vs. anti-TCRγδ vs. anti–IL-17A plus anti-TCRγδ; P = 0.20, by log-rank test). Neonatal mice received 100 μg antibody on day –2, followed by a second dose on day 0.