Project description:Type-2 innate lymphoid cells (ILC2s) have emerged as key immune-response regulators in renal-inflammatory diseases such as lupus nephritis. However, the adhesion and migration of ILC2s, including in the homeostatic and diseased kidney, are poorly understood. By integrating transcriptomic profiling, flow cytometry, live-cell imaging, and in-vivo models, we showed that renal ILCs are retained in the homeostatic kidney by the adherence of their cell-surface integrin α4β7 to VCAM-1, E-cadherin or fibronectin on structural kidney cells. When cultured on these ligands, ILC2s demonstrated remarkable migration. Knocking down integrin-α4β7 expression reduced ILC2 Areg production. In lupus nephritis, TLR7/9 may downregulate ILC2 expression of integrin-α4β7, thereby both reducing Areg expression and promoting ILC2 egress. Areg loss may promote the proinflammatory-cytokine secretion by T cells. IL-33 upregulated ILC2 integrin-α4β7 and Areg expression. Notably, IL-33 treatment enhanced survival in lupus nephritis by mitigating kidney inflammation. Thus, ILC2 adhesion may be a therapeutic target for autoimmune kidney diseases.
Project description:This series represents mature CD4+ lymphocytes with high and low expression of integrin α4β7 isolated from human subjects. Keywords = lymphocyte, integrin α4β7 , differential gene expression, microarray Keywords: parallel sample
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
Project description:The anti-HIV humoral immune response following acute infection is delayed and ineffective. HIV envelope protein gp120 binds to and signals through α4β7 on T cells. We show that gp120 also binds and signals through α4β7 on B cells, resulting in an abortive proliferative response. In primary B cells, gp120 signaling through α4β7 resulted in increased expression of TGF-β1 and the B cell inhibitory receptor FcRL4. Co-culture of B cells with HIV-infected autologous CD4+ T cells also resulted in increased B cell FcRL4 expression. These findings indicate that, in addition to inducing chronic immune activation, viral proteins can contribute directly to HIV-associated B cell dysfunction, thus providing a mechanism whereby the virus subverts the early HIV-specific humoral immune response. Forty-two samples in two batches were run with different treatments and different time points.
Project description:Transcriptional profiling of transgenic mice specifically expressing amphiregulin in white adipose tissues. The objective of this study is to explore gene expression profiles of adipose tissues in response to amphiregulin overexpression.
Project description:Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, β6 integrin is restricted to epithelia and partners exclusively with integrin αV to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking β6 integrin (β6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found β6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial β6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor-β regulation. Expression of β6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of β6 function may therefore provide a means to improve outcomes in lung microbial infections. We used microarrays to explore the gene expression profiles differentially expressed in resident alveolar macrophage cells from wild-type and β6 integrin knockout mice. Cells were purified by sorting from lung digests. The comparison made was CD11c+, autofluorescent+ cells from wild-type controls to the dominant CD11c+, CD11b+, autofluorescent+ cells in the knockout. Note that conventional CD11c+ alveolar macrophages do not exist in the knockout mice.
Project description:Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, β6 integrin is restricted to epithelia and partners exclusively with integrin αV to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking β6 integrin (β6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found β6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial β6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor-β regulation. Expression of β6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of β6 function may therefore provide a means to improve outcomes in lung microbial infections.
Project description:NZB/WF1 female mice spontaneously develop autoimmune lupus nephritis. Expression profiling of kidney tissue from (a) 12 week NZB/W F1 female mice defined as asymptomatic for lupus nephritis, (b) 36 and 42 week NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 and 42 week NZB/W F1 female mice that are diseased/symptomatic for lupus nephritis and treated with Sirolimus was carried out. The goal of the study was to identify genes associated with lupus nephritis and modulated by Sirolimus, an inhibitor of mTOR. In addition, lupus nephritis genes resistant to Sirolimus therapy were also identfied This series of samples comprises of kidney tissue from (a) 12 week old NZB/W F1 female mice defined as asymptomatic for lupus nephritis (N=4), (b) 36 (N=3) and 42 week (N=3) old NZB/W F1 female mice defined as diseased/symptomatic for lupus nephritis and (c) 36 (N=3)and 42 (N=3) week old NZB/W F1 female mice that are asymptomatic for lupus nephritis on treatment with Sirolimus