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Adoptive cellular therapy utilizing chimeric antigen receptor redirected T (CAR-T) cells has shown impressive therapeutic effects on hematological malignancies. In contrast, the efficacy of CAR-T therapies in treating solid tumors is still poor, which is largely due to inefficient penetration into solid tumors and the immunosuppressive tumor microenvironment. Herein, we engineered hyaluronidase (HAase) and the checkpoint blocking antibody α-PDL1 on the CAR-T cell surface via highly efficient and biocompatible bioorthogonal click chemistry to improve their therapeutic effects on solid tumors. The modified HAase degrades hyaluronic acid and destroys the tumor extracellular matrix, allowing CAR-T cells to penetrate deeply into solid tumors, as evidenced by

Pyruvate dehydrogenase (PDC)-E2 specific CD8Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103Intrahepatic CD103CD103Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8

Increasing evidence demonstrates that IL-17A promotes tumorigenesis, metastasis, and viral infection. Natural killer (NK) cells are critical for defending against tumors and infections. However, the roles and mechanisms of IL-17A in regulating NK cell activity remain elusive. Herein, our study demonstrated that IL-17A constrained NK cell antitumor and antiviral activity by restraining NK cell maturation. It was observed that the development and metastasis of tumors were suppressed in IL-17A–deficient mice in the NK cell-dependent manner. In addition, the antiviral activity of NK cells was also improved in IL-17A–deficient mice. Mechanistically, ablation of IL-17A signaling promoted generation of terminally mature CD27(−)CD11b(+) NK cells, whereas constitutive IL-17A signaling reduced terminally mature NK cells. Parabiosis or mixed bone marrow chimeras from Il17a(−/−)and wild-type (WT) mice could inhibit excessive generation of terminally mature NK cells induced by IL-17A deficiency. Furthermore, IL-17A desensitized NK cell responses to IL-15 and suppressed IL-15–induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) via up-regulation of SOCS3, leading to down-regulation of Blimp-1. Therefore, IL-17A acts as the checkpoint during NK cell terminal maturation, which highlights potential interventions to defend against tumors and viral infections.

The diverse inflammatory response found in the liver of patients with autoimmune hepatitis (AIH) is well established, but identification of potentially pathogenic subpopulations has proven enigmatic.We report herein that CD69Our data suggest that CD8

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance. Natural killer cells may respond better on second antigen encounters, but how this memory is induced or maintained in vivo is not clear. Here the authors show that memory NK cells expressing interleukin-7 (IL-7) receptor are induced in the lymph nodes but later recruited to liver for long term, IL-7 dependent survival and memory maintenance.

The microbiota control regional immunity using mechanisms such as inducing IL-17A-producing γδ T (γδT-17) cells in various tissues. However, little is known regarding hepatic γδT cells that are constantly stimulated by gut commensal microbes. Here we show hepatic γδT cells are liver-resident cells and predominant producers of IL-17A. The microbiota sustain hepatic γδT-17 cell homeostasis, including activation, survival and proliferation. The global commensal quantity affects the number of liver-resident γδT-17 cells; indeed, E. coli alone can generate γδT-17 cells in a dose-dependent manner. Liver-resident γδT-17 cell homeostasis depends on hepatocyte-expressed CD1d, that present lipid antigen, but not Toll-like receptors or IL-1/IL-23 receptor signalling. Supplementing mice in vivo or loading hepatocytes in vitro with exogenous commensal lipid antigens augments the hepatic γδT-17 cell number. Moreover, the microbiota accelerate nonalcoholic fatty liver disease through hepatic γδT-17 cells. Thus, our work describes a unique liver-resident γδT-17 cell subset maintained by gut commensal microbes through CD1d/lipid antigens.

Liver-resident natural killer (LrNK) cells are a unique subset of NK cells that are distinct from conventional NK cells. However, little is known about the mechanisms by which LrNK cells mature. In this study, we discovered that LrNK cells exhibit a relatively immature phenotype and impaired cytotoxic capacity in the absence of CD8

Hepatitis B virus (HBV) persistence is a fundamental process in chronic HBV infection and a key factor in all related liver diseases; however, the mechanisms have yet to be elucidated. We studied the role of TLR2 in HBV persistence using a well-established HBV-carrier mouse model generated by hydrodynamically injecting a phospho–adeno-associated virus/HBV1.2 plasmid into mice. We found that a genetic deficiency in TLR2 improves HBV elimination, whereas activating TLR2 led to more stable HBV persistence, suggesting that TLR2 activation is critical in HBV persistence. Furthermore, we noted that TLR2 activation could inhibit CD8+ T cell function, causing the exhaustion phenotype in HBV-carrier mice, because TLR2 deficiency might rescue CD8+ T cell function in a cellular adoptive experiment. TLR2 expression on Kupffer cells (KCs) was upregulated in HBV-carrier mice, which accounts for HBV persistence, because the difference in anti-HBV immunity between HBV-carrier wild-type and Tlr2−/− mice did not exist after KC depletion. In addition, similar to TLR2 deficiency, after KC depletion, CD8+ T cells were more efficiently activated in HBV-carrier mice, leading to rapid HBV elimination. KCs produced more IL-10 upon TLR2 activation in response to direct hepatitis B core Ag stimulation, and the elevated IL-10 inhibited CD8+ T cell function in HBV-carrier mice, because IL-10 deficiency or anti–IL-10R treatment resulted in CD8+ T cells with stronger antiviral function. In conclusion, KCs support liver tolerance by inducing anti-HBV CD8+ T cell exhaustion via IL-10 production after TLR2 activation by hepatitis B core Ag stimulation.

Background & Aims It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1β release in alcoholic liver injury; however, how IL-1β promotes liver injury remains unclear. Methods We investigated the role of IL-1β in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model. Results Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient Jα18 −/− mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1β were required for the hepatic iNKT accumulation, as either blocking IL-1β signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1β in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1β overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1β correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol–exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells. Conclusions After alcohol–exposure Kupffer cell-derived IL-1β triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.

The contribution of innate immune cells to acetaminophen (APAP)-induced liver injury has been extensively investigated. However, the roles of T cell populations among adaptive immune cells in APAP-induced liver injury remain to be elucidated. Herein, we found that distinct CD4(+) T cell subsets but not CD8(+) T cells modulated APAP-induced liver injury in mice. After APAP challenge, more CD62L(low)CD44(hi)CD4(+) T cells appeared in the liver, accompanied by increased IFN-γ. The removal of CD4(+) T cells by either antibody depletion or genetic deficiency markedly compromised pro-inflammatory cytokine levels and ameliorated liver injury. Meanwhile, we also found that the frequency and absolute number of Treg cells also increased. Treg cell depletion increased hepatic CD62L(low)CD44(hi)CD4(+) T cells, augmented pro-inflammatory cytokines, and exacerbated liver injury, while adoptive transfer of Treg cells ameliorated APAP-induced liver injury. Furthermore, the recruitment of Treg cells into the liver through specific expression of CXCL10 in the liver could ameliorate APAP-induced liver injury. Our investigation suggests that Th1 and Treg subsets are involved in regulating APAP-induced liver injury. Thus, modulating the Th1/Treg balance may be an effective strategy to prevent and/or treat APAP-induced liver injury.

Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC., Primary biliary cholangitis is an autoimmune liver disease. Here, the authors show that variants in interleukin genes which potentially deregulate their expression are associated with this condition, and suggest that the IL21 signalling pathway may have a role in disease aetiology.

Tumor-associated macrophages, crucial components of the microenvironment in hepatocellular carcinoma, hamper anti-cancer immune responses. The aim of the present study was to investigate the effect of sorafenib on the formation of the tumor microenvironment, especially the relationship between polarized macrophages and hepatocytes. Macrophage infiltration was reduced in patients with hepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenib abolished polarized macrophage-induced epithelial mesenchymal transition (EMT) and migration of hepatocellular carcinoma cells but not normal hepatocytes. Moreover, sorafenib attenuated HGF secretion in polarized macrophages, and decreased plasma HGF in patients with hepatocellular carcinoma. Additionally, sorafenib abolished the polarized macrophage-induced activation of the HGF receptor Met in hepatocellular carcinoma cells. Our findings suggest that sorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinoma cells via the HGF-Met signaling pathway. These results contribute to our understanding of the immunological mechanisms that underlie the protective effects of sorafenib in hepatocellular carcinoma therapy.

We previously described the NOD.c3c4 mouse, which is protected from type 1 diabetes (T1D) because of protective alleles at multiple insulin-dependent diabetes (Idd) genes, but develops autoimmune biliary disease (ABD) resembling primary biliary cirrhosis (PBC). In this paper, we characterize the NOD.ABD strain, which is genetically related to the NOD.c3c4 strain but develops both ABD and T1D. Histologically, NOD.ABD biliary disease is indistinguishable from that in NOD.c3c4 mice. The frequency of effector memory (CD44+CD62L−) and central memory (CD44+CD62L+) CD8 T cells is significantly increased in the intrahepatic lymphocyte fraction of NOD.ABD mice, and NOD.ABD CD8 T cells produce more IFN-γ and TNF-α, compared with controls. NOD.ABD splenocytes can transfer ABD and T1D to NOD.c3c4 scid mice, but only T1D to NOD scid mice, suggesting that the genetic origin of the target organ and/or its innate immune cells is critical to disease pathogenesis. The disease transfer model, importantly, shows that biliary duct damage (characteristic of PBC) and inflammation precede biliary epithelial cell proliferation. Unlike T1D where both CD4 and CD8 T cells are required for disease transfer, purified NOD.ABD CD8 T cells can transfer liver inflammation into NOD.c3c4 scid recipients, and disease transfer is ameliorated by cotransferring T regulatory cells. Unlike NOD.c3c4 mice, NOD.ABD mice do not develop anti-nuclear or anti-Smith autoantibodies; however, NOD.ABD mice do develop the antipyruvate dehydrogenase Abs typical of human PBC. The NOD.ABD strain is a model of immune dysregulation affecting two organ systems, most likely by mechanisms that do not completely coincide.

There are now several murine models of autoimmune cholangitis that have features both similar and distinct from human PBC. One such model, the NOD.c3c4 mouse, manifests portal cell infiltrates, anti-mitochondrial antibodies but also biliary cysts. The biliary cysts are not a component of PBC and not found in the other murine models. To address the immunopathology in these mice, we generated genetically B cell deficient Igμ(-/-) NOD.c3c4 mice and compared the immunopathology of these animals to control B cell sufficient NOD.c3c4 mice. B cell deficient mice demonstrated decreased number of non-B cells in the liver accompanied by reduced numbers of activated natural killer cells. The degree of granuloma formation and bile duct damage were comparable to NOD.c3c4 mice. In contrast, liver inflammation, biliary cyst formation and salivary gland inflammation was significantly attenuated in these B cell deficient mice. In conclusion, B cells play a critical role in promoting liver inflammation and also contribute to cyst formation as well as salivary gland pathology in autoimmune NOD.c3c4 mice, illustrating a critical role of B cells in modulating specific organ pathology and, in particular, in exacerbating both the biliary disease and the sialadenitis.

Uncontrolled immune responses to intracellular DNA have been shown to induce autoimmune diseases. Homeostasis regulation of immune responses to cytosolic DNA is critical for limiting the risk of autoimmunity and survival of the host. Here, we report that the E3 ubiquitin ligase tripartite motif protein 30α (TRIM30α) was induced by herpes simplex virus type 1 (HSV-1) infection in dendritic cells (DCs). Knockdown or genetic ablation of TRIM30α augmented the type I IFNs and interleukin-6 response to intracellular DNA and DNA viruses. Trim30α-deficient mice were more resistant to infection by DNA viruses. Biochemical analyses showed that TRIM30α interacted with the stimulator of interferon genes (STING), which is a critical regulator of the DNA-sensing response. Overexpression of TRIM30α promoted the degradation of STING via K48-linked ubiquitination at Lys275 through a proteasome-dependent pathway. These findings indicate that E3 ligase TRIM30α is an important negative-feedback regulator of innate immune responses to DNA viruses by targeting STING., Author Summary Negative-feedback regulation is a broad and pivotal biological event to maintain the homeostasis of the host. Viral DNA species derived from DNA viruses or retroviruses can activate STING signaling to produce pro-inflammatory cytokines and type I interferon, which further recruit immune cells or induce interferon stimulated genes (ISGs) to clear viral infection respectively. However, excessive STING-signaling activation has been shown to induce autoimmune disorders. Thus, it is important to finely turn off STING signaling. Here we demonstrate that TRIM30α is rapidly induced followed by STING activation. Trim30α-deficient mice show more resistance to infection by DNA viruses. Meanwhile, knockdown or genetic ablation of TRIM30α augments the type I IFNs and IL-6 responses to intracellular DNA and DNA viruses. Biochemical analyses show that TRIM30α interacts with STING and promotes the degradation of STING via K48-linked ubiquitination at Lys275. These findings demonstrate that induced TRIM30α is a negative-feedback regulator of STING pathway activation triggered by DNA and DNA viruses, which helps the host to avoid excessive response and maintain homeostasis.

Disruption of peripheral blood B-cell homeostasis and variation of surface receptors occur with certain infections and autoimmune diseases. However, the impact of antiviral therapy on B-cell alteration during chronic hepatitis B (CHB) infection remains unclear. Our study aims to document the effects of B-cell alteration in CHB patients treated with tenofovir or adefovir. A total of 21 CHB patients and 10 healthy donors were recruited into the study. We identified B-cell subsets by flow cytometry and observed changes in the B-cell repertoire of CHB patients upon tenofovir or adefovir antiviral treatment. The total and percent of B cells and CD5 + B-cell subsets were significantly increased in CHB patients compared to healthy donors. Total and percent of CD5 + B cells gradually decreased following the diminution of the HBV DNA load after tenofovir and adefovir treatment. Upon tenofovir treatment, the percent of memory CD27 + B cells was increased but the absolute number declined, whereas naïve CD27− B cells declined in both percent and absolute number. In the adefovir treatment group, neither naïve nor memory B cells were altered by the treatment. Furthermore, CHB patients displayed higher levels of activation markers (CD69 and CD24) and trended towards restored B-cell homeostasis after antiviral treatment. In conclusion, disrupted B-cell homeostasis is an important feature of CHB patients and is partially restored after control of viral replication by antiviral treatment. B-cell antiviral immunity is improved by restoring B-cell homeostasis and activation.

There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8(+) T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1(-/-) recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8(+) T cells or due to the abnormal TGFβR environment within which CD8(+) T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1(-/-) , OT-II/Rag1(-/-) mice and in addition generated OT-I/dnTGFβRII/Rag1(-/-) , and OT-II/dnTGFβRII/Rag1(-/-) mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8(+) or CD4(+) T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1(-/-) mice and/or OT-II/dnTGFβRII/Rag1(-/-) mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8(+) T cells from dnTGFβRII mice but not CD8(+) T cells from OT-I/Rag1(-/-) mice or from OT-I/dnTGFβRII/Rag1(-/-) mice transferred disease. These data were not secondary to an absence of CD4(+) T cell help since a combination of CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) and CD4(+) T cells from OT II/dnTGFβRII/Rag1(-/-) or CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) with CD4(+) T cells from OT-II/Rag1(-/-) mice failed to transfer disease.Defective TGFβRII signaling, in addition to clonal CD8(+) T cells that target biliary cells, are required for induction of autoimmune cholangitis.

Dominant-negative TGF-β receptor II (dnTGF-βRII) mice spontaneously develop an autoimmune cholangitis resembling human primary biliary cirrhosis (PBC). Interestingly, the dominant-negative TGF-β receptor is expressed by both CD4(+) and CD8(+) T cells and leads to greatly reduced (but not absent) TGF-β signaling resulting in T cell intrinsic cell mediated autoimmunity. However, the mechanisms of the T cell dysregulation remain unclear. Recently it has been shown that TGF-β signaling is intimately involved with miRNA biogenesis and control. Herein we show that lack of T cell TGF-β signaling leads to down regulation of T cell miRNAs but up-regulation of the key inflammatory miRNA 21. Furthermore, the expression of miR-21 from hepatic effector CD8(+) T cells is significantly higher than in the same subsets isolated from spleen and mesenteric lymph nodes of the dnTGF-βRII mice. Previous studies indicate that miR-21 increases the synthesis of IFN-γ and IL-17A by T cells and suppresses apoptosis via programmed cell death protein 4 (PDCD4). Data presented herein demonstrate that transfecting w.t. B6 T cell subsets with miR-21 resulted in up-regulation of the inflammatory cytokines TNF-α and IFN-γ, thus partly replicating the dnTGF-βRII T cell phenotype. In conclusion, these data suggest miR-21 plays a critical role in the production of pro-inflammatory cytokines in dnTGF-βRII mice, which could be a contributing factor for the development of the organ-specific autoimmune cholangitis and colitis in this murine model of human PBC.

Primary biliary cirrhosis (PBC) is a female-predominant organ-specific autoimmune disease characterized by destruction of intrahepatic small bile duct biliary epithelial cells (BECs) (1). The serological hallmark of PBC is the presence of anti-mitochondrial auto-antibodies (AMA) directed against the pyruvate dehydrogenase E2 complex (PDC-E2) located in the inner membrane of mitochondria (2–4). High frequency of CD4+ and CD8+ T cell infiltrates have been noted within the portal tracts of PBC liver, which strongly suggests that these cells are involved in the pathogenesis of PBC (5). Indeed PDC-E2 specific autoreactive CD4+ T and CD8+ T cells have been identified both in peripheral blood and, at much higher levels, in liver of PBC patients (6–8). The dominant CD4+ and CD8+ T cell epitopes on PDC-E2 has been mapped (6–8). While both CD4+ and CD8+ T cells are present within portal tract infiltrates, there is a growing body of data that suggests a more direct role of cytotoxic CD8+ T cells in biliary destruction (9–11). The study of effector pathways is a particularly challenging problem in human autoimmunity. For one thing, the majority of effector pathways are likely to be mediated by non-specific bystander cells recruited during inflammation. For another, it has been difficult to identify subpopulations of cells by phenotype and thence link such data to functionality. Our laboratory has focused attention on effector T cell populations using a variety of technologies and has highlighted the important role of T cells in this and similar pathways. In this study we took advantage of newer reagents including cell surface markers that are associated with CD8high effector memory T cells (TEM), organ and tissue specific homing and alterations in susceptibility to apoptosis. Indeed, we report that patients with PBC not only have an increased frequency of CD45ROhighCD57+CD8high T cells compared to controls, but also that such cells have increased α4β7 expression with concurrently increased expression of CCR5 and decreased expression of CCR7 and CD28 compared to other CD8high T cells. Further, this T cell subset has increased production of granzyme A, granzyme B and perforin compared with other CD8high T cells and interestingly have decreased stimulation-induced apoptosis. Furthermore, IFN-γ and IL-5 produced by CD8+CD57+ T lymphocytes upon in vitro TCR stimulation are increased in PBC patients. Histologically, CD8+CD57+ T cells accumulate around the portal area in the liver of PBC patients. Moreover, purified CD8+CD57+ T cells from PBC patients specifically respond to the MHC class I restricted epitope of PDC-E2. These data have implications for understanding CD8 effector pathways in this autoimmune disease. We submit that CD45ROhighCD57+CD8high T cells are a subset of cytotoxic memory cells which play a critical role in the chronic and progressive destruction of BECs in PBC.

In recent decades, an enormous effort has been made to elucidate the pathogenesis of autoimmune and autoinflammatory diseases. Autoimmunity is a multifactorial process in which genetic, immunological, environmental and hormonal factors play in concert, together representing what was termed years ago the ‘mosaic of autoimmunity'. To date, more than 80 systemic and organ-specific autoimmune diseases have been defined, and their cumulative burden is substantial, both medically and financially. Furthermore, the burden of autoimmune and autoinflammatory diseases is rising, making these diseases a ubiquitous global phenomenon that is predicted to further increase in the coming decades. In this issue of the journal, additional aspects of autoimmunity are detailed. Immune dysregulation and loss of self-tolerance are the cornerstones of autoimmunity.

Wang et al. examine how influenza A virus causes GI symptoms. Intranasal infection in mice causes intestinal pathology via virally activated CD4 T cells in the lung up-regulating CCR9 and migrating to the intestine where they secrete IFN-γ that alters homeostasis of the microbiota. Subsequent induction of IL-15 aids differentiation into pathogenic Th17 cells in the gut., Influenza in humans is often accompanied by gastroenteritis-like symptoms such as diarrhea, but the underlying mechanism is not yet understood. We explored the occurrence of gastroenteritis-like symptoms using a mouse model of respiratory influenza infection. We found that respiratory influenza infection caused intestinal injury when lung injury occurred, which was not due to direct intestinal viral infection. Influenza infection altered the intestinal microbiota composition, which was mediated by IFN-γ produced by lung-derived CCR9+CD4+ T cells recruited into the small intestine. Th17 cells markedly increased in the small intestine after PR8 infection, and neutralizing IL-17A reduced intestinal injury. Moreover, antibiotic depletion of intestinal microbiota reduced IL-17A production and attenuated influenza-caused intestinal injury. Further study showed that the alteration of intestinal microbiota significantly stimulated IL-15 production from intestinal epithelial cells, which subsequently promoted Th17 cell polarization in the small intestine in situ. Thus, our findings provide new insights into an undescribed mechanism by which respiratory influenza infection causes intestinal disease.