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Tumor-associated neutrophils suppress pro-tumoral IL-17+ ?? T cells through induction of oxidative stress.

ABSTRACT: Interleukin 17 (IL-17)-producing ?? T cells (??17 T cells) have been recently found to promote tumor growth and metastasis formation. How such ??17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing ??17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27- V?6+ ??17 T cells via induction of oxidative stress, thereby preventing them from constituting the major source of pro-tumoral IL-17 in the tumor microenvironment. Mechanistically, we found that low expression of the antioxidant glutathione in CD27- ??17 T cells renders them particularly susceptible to neutrophil-derived reactive oxygen species (ROS). Consistently, superoxide deficiency, or the administration of a glutathione precursor, rescued CD27- V?6+ ??17 T-cell proliferation in vivo. Moreover, human V?1+ ?? T cells, which contain most ??17 T cells found in cancer patients, also displayed low glutathione levels and were potently inhibited by ROS. This work thus identifies an unanticipated, immunosuppressive yet antitumoral, neutrophil/ROS/??17 T-cell axis in the tumor microenvironment.

SUBMITTER: Mensurado S

PROVIDER: S-EPMC5965901 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress.

Mensurado Sofia S Rei Margarida M Lança Telma T Ioannou Marianna M Gonçalves-Sousa Natacha N Kubo Hiroshi H Malissen Marie M Papayannopoulos Venizelos V Serre Karine K Silva-Santos Bruno B

PLoS biology 20180511 5

Interleukin 17 (IL-17)-producing γδ T cells (γδ17 T cells) have been recently found to promote tumor growth and metastasis formation. How such γδ17 T-cell responses may be regulated in the tumor microenvironment remains, however, largely unknown. Here, we report that tumor-associated neutrophils can display an overt antitumor role by strongly suppressing γδ17 T cells. Tumor-associated neutrophils inhibited the proliferation of murine CD27- Vγ6+ γδ17 T cells via induction of oxidative stress, the ...[more]

PMID: 29750788

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Project description:Coxiella burnetii is a highly infectious pathogen that causes Q fever, a leading cause of culture-negative endocarditis. Coxiella first targets alveolar macrophages and forms a phagolysosome-like compartment called the C oxiella - C ontaining V acuole (CCV). Successful host cell infection requires the Type 4B Secretion System (T4BSS), which translocates bacterial effector proteins across the CCV membrane into the host cytoplasm, where they manipulate numerous cell processes. Our prior transcriptional studies revealed that Coxiella T4BSS blocks IL-17 signaling in macrophages. Given that IL-17 is known to protect against pulmonary pathogens, we hypothesize that C. burnetii T4BSS downregulates intracellular IL-17 signaling to evade the host immune response and promote bacterial pathogenesis. Using a stable IL-17 promoter reporter cell line, we confirmed that Coxiella T4BSS blocks IL-17 transcription activation. Assessment of the phosphorylation state of NF-κB, MAPK, and JNK revealed that Coxiella downregulates IL-17 activation of these proteins. Using ACT1 knockdown and IL-17RA or TRAF6 knockout cells, we next determined that IL17RA-ACT1-TRAF6 pathway is essential for the IL-17 bactericidal effect in macrophages. In addition, macrophages stimulated with IL-17 generate higher levels of reactive oxygen species, which is likely connected to the bactericidal effect of IL-17. However, C. burnetii T4SS effector proteins block the IL-17-mediated oxidative stress, suggesting that Coxiella blocks IL-17 signaling to avoid direct killing by the macrophages.ImportanceBacterial pathogens are constantly evolving mechanisms to modulate the hostile host environment encountered during infection. Coxiella burnetii , the causative agent of Q fever, is a fascinating example of intracellular parasitism. Coxiella survives in a phagolysosome-like vacuole and uses the Dot/Icm type IVB secretion system (T4BSS) to deliver bacterial effector proteins into the host cell cytoplasm to manipulate several host cell functions. We recently demonstrated that Coxiella T4BSS blocks the IL-17 signaling in macrophages. Here, we found that Coxiella T4BSS inhibits IL-17 activation of the NF-κB and MAPK pathways and blocks IL-17-mediated oxidative stress. These findings reveal a novel strategy employed by intracellular bacteria to escape the immune response during initial stages of infection. Further identification of virulence factors involved in this mechanism will bring to light new therapeutic targets to prevent Q fever development into a chronic life-threatening endocarditis.

Dataset Information

Tumor-associated neutrophils suppress pro-tumoral IL-17+ ?? T cells through induction of oxidative stress.

Publications

Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress.

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