IL-17 Promotes Neutrophil Entry into Tumor-Draining Lymph Nodes following Induction of Sterile Inflammation

Brackett, Craig M.; Muhitch, Jason B.; Evans, Sharon S.; Gollnick, Sandra O.

doi:10.4049/jimmunol.1103621

Cited by 66 publications

(77 citation statements)

References 73 publications

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“…Accordingly, the IL17-induced CCL-2 and CXCL-2 chemokines, were decreased in tumor supernatants from mice lacking MHCII on pDCs. Decrease in CCL-2 and CXCL-2, which induce the recruitment of lymphocytes, myeloid cells (53)(54)(55), and neutrophils (56), respectively, may explain impaired recruitment of several immune cell populations into tumors in mice lacking MHCII on pDCs. Altogether, our data demonstrated that MHCII þ pDC-derived, tumor-specific Th17 cells increase overall immune tumor infiltrate, including CTLs that would then mediate tumor rejection.…”

Section: Discussionmentioning

confidence: 99%

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

et al. 2014

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Plasmacytoid dendritic cells (pDC) rapidly and massively produce type I IFN and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing T-cell responses. Moreover, antigen (Ag)-presenting pDCs directly regulate T-cell differentiation. Depending on the immune environment, pDCs exhibit either tolerogenic or immunogenic properties. Here, we show that CpG-activated pDCs promote efficient Th17 differentiation. Indeed, Th17 responses are defective in mice selectively lacking MHCII on pDCs upon antigenic challenge. Importantly, in those mice, the frequency of Th17 cells infiltrating solid tumors is impaired. As a result, the recruitment of infiltrating leukocytes in tumors, including tumor-specific cytotoxic T lymphocytes (CTL), is altered and results in increased tumor growth. Importantly, following immunization with tumor Ag and CpG-B, MHCII-restricted Ag presentation by pDCs promotes the differentiation of antitumor Th17 cells that induce intratumor CTL recruitment and subsequent regression of established tumors. Our results highlight a new role for Ag presenting activated pDCs in promoting the development of Th17 cells and impacting on antitumor immunity. Cancer Res; 74(22); 6430-40. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

et al. 2014

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“…These chemokines were all induced in K14.E7 skin after DNCB treatment, However, IL-17A deficiency and suppression of arginase-1 in K14.E7 skin significantly reduced the expression of CXCL1 and CXCL5, suggesting that CXCL1 and CXCL5 are important mediators for IL-17A and arginase to promote the hyperinflammation in K14.E7 skin. Our findings are supported by previous studies that IL-17A promotes neutrophil infiltration via CXCL1 (184) or CXCL5 (185) induction during acute inflammatory responses.…”

Section: Hpv16e7-induced Cutaneous Hyperinflammation To Dncb Is Assosupporting

confidence: 92%

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Tran¹

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Persistent infection with oncogenic human papillomaviruses (HPV), particularly HPV16, is associated with selective expression of two virally encoded proteins (E6 and E7). One action of HPV16.E7 protein is to subvert the innate immune system through the down-regulation of IFNγ pathways, modulation of antigen presentation, and suppression of Toll-like receptor 9 protein.K14.E7 transgenic mice, which express HPV16.E7 oncoprotein within basal keratinocytes under the control of the keratin 14 transcriptional promoter, have been extensively used as a model of HPV oncoprotein-induced immune suppression associated with human squamous cancers, in which only the E6 and E7 genes of the papillomavirus are expressed. It has previously been shown that skin grafts expressing HPV16.E7 oncoprotein are not spontaneously rejected when transplanted onto syngeneic animals, but they are rejected when certain components of the innate immune system are unavailable, confirming that the expression of HPV16.E7 in the epithelium results in the establishment of a local suppressive environment and the subversion of antigen-specific T cells. Therefore, successful strategies targeting HPV-associated cancer need to circumvent or disrupt the local suppressive environment.Topical immunotherapy with immunostimulatory agents has been used clinically to treat cancerous lesions including squamous cell and basal cell carcinoma in immunocompetent and immunosuppressed patients. Topical application of 2,4-dinitrochlorobenzene (DNCB) is an effective therapy for condylomata acuminata caused by HPV infection. DNCB induced the complete clearance of HPV-associated warts in 13/15 patients. However, the use of DNCB for treatment has been discouraged because of its mutagenic potential. The aim of my doctoral research is to understand the mechanism of DNCB-induced inflammation in K14.E7 transgenic mice which has been poorly understood. I hypothesized that understanding how induction of a vigorous acute inflammatory response by DNCB can break the local immune-suppressive environment and restore the effector function of adaptive immunity might lead to more acceptable treatments for persisting HPV infection. In support of this hypothesis, the present study showed that DNCB application along with E7 specific immunization therapy was capable of inducing HPV16.E7 skin graft rejection.Arginase, which metabolizes l-arginine to N-ornithine and urea, has been identified as a crucial regulator of inflammation. As inflammation decides the fate of HPV infection and arginase is an important regulator of inflammation and immunity, I investigated the ii interaction between DNCB-induced inflammation and HPV16.E7 protein in the induction of arginase in K14.E7 transgenic mice. The first part of this study showed that topical DNCB application to skin expressing HPV16.E7 as a transgene induces a hyperinflammatory response, which is not seen in nontransgenic control animals. The E7-associated Taken together, my study suggests that HPV16.E7 protein enhances DNCB associated-prod...

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“…This could be related to the IL-17 made by T cells in the draining lymph nodes (SI Appendix, Fig. S13C) following reconstitution of nonspecific transduced neutrophils and, to a lesser extent, FOXO1 knockdown neutrophils, because this cytokine has been shown to promote neutrophil migration into draining lymph nodes (47).…”

Section: Foxo1-deficient Neutrophils Fail To Induce Nit Cells and To mentioning

confidence: 99%

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

Nadkarni

Sferruzzi‐Perri

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

117

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Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil–T cell interactions in the regulation of vascularization at the maternal–fetal interface.

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IL-17 Promotes Neutrophil Entry into Tumor-Draining Lymph Nodes following Induction of Sterile Inflammation

Cited by 66 publications

References 73 publications

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

Ag-Presenting CpG-Activated pDCs Prime Th17 Cells That Induce Tumor Regression

Mechanisms of 2,4-Dinitrochlorobenzene-induced acute inflammation in Human Papillomavirus type 16 E7 oncoprotein expressing skin

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

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