Project description:The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T-cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms, and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Oxygen tension is one important factor influencing immune responses. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected γδ T-cell-mediated antitumor immune responses but not those of conventional T-cells. Specifically, tumor hypoxia activated the γδ T-cell protein kinase A (PKA) pathway at a transcriptional level, resulting in repression of NKG2D expression. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of γδ T-cells. These results reveal a hypoxia-mediated mechanism by which brain tumors and γδ T-cells interact and emphasize the importance of γδ T-cells for antitumor immunity against brain tumors.
Project description:Obesity is detrimental to the immune system. It impairs lymphatics, T cell development, and lymphopoiesis; induces dysfunction of antitumor immunity; and also promotes tumor progression. However, direct evidence of the impact of obesity on viral infection is lacking. We found an unexpected protective role of obesity against herpes simplex virus 2 infection of the genital mucosa in mice. Although conventional antiviral immunity was comparable between obese mice and lean mice, obesity enhanced the cytotoxic subset of γδ T cells. This effect was mediated by L-arginine produced by commensal microbiota in the genital mucosa, which induced “pseudonormoxia” of γδ T cells, resulting in increased NKG2D expression of γδ T cells through the downregulation of HIF1A by inducing NO production, thereby protecting mice from lethal genital herpes. Thus, our work illuminates one mechanism by which obesity-induced compositional changes in the vaginal microbiota can affect mucosal immune responses against viral infection.
Project description:The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. In this study, we used microarrays to uncover the transcriptional responses that occur in small intestinal γδ intraepithelial lymphocytes following bacterial challenge. γδ intraepithelial lymphocytes (γδ IEL) were isolated by flow cytometry from the small intestines of germ-free mice, or from age- and sex-matched conventionally-raised counterparts. We extracted RNAs from these purified γδ IEL for analysis on Affymetrix DNA microarrays. The mice were all >8 weeks in age, and each sample represents a pool of RNAs from 5-8 mice.
Project description:Triple negative breast cancer (TNBC) lacks targeted therapy options. TNBC is enriched in breast cancer stem cells (BCSCs), which play a key role in metastasis, chemoresistance, relapse and mortality. γδ T cells hold great potential in immunotherapy against cancer, and might be an alternative to target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor sensing, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. We show that patient derived triple negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T cell immunotherapy. Mechanistically, we unraveled concerted differentiation and immune escape: xenografted BCSCs lost stemness, expression of γδ T cell ligands, adhesion molecules and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither pro-migratory engineered γδ T cells, nor anti-PD 1 checkpoint blockade significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells, and could be pharmacologically reverted by Zoledronate or IFN-α treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
Project description:γδ T cells producing interleukin 17A (IL-17A), which are mainly Vγ4 and Vγ6 subsets, are involved in protection against infection by extracellular bacteria. Using a new Vγ6-specific monoclonal antibody (mAb) (1C10-1F7) which we recently developed, we found that IL-17A+ Vγ6+ γδ T cells increased predominantly in the peritoneal cavity compared with IL-17A+ Vγ4+ γδ T cells during intraperitoneal Escherichia coli infection. The number of IL-17A+ Vγ6+ γδ T cells, which rapidly became CD69+ from CD69-, peaked at 12 h after infection. In vivo treatment with 1C10-1F7 mAb significantly inhibited the accumulation of neutrophils and hampered the resolution of E. coli infection. These results suggest that rapid activation of IL-17A+ Vγ6+ γδ T cells contributed to host defence against E. coli infection.
Project description:Influenza infection causes high rates of hospitalization and mortality in infants. γδ T cells are critical for immune responses against pathogens as regulators and effectors, especially in infants, and yet the roles of neonatal γδ T cells in influenza remain to be investigated. Here we report that γδ T cells were protective against mortality associated with neonatal influenza infection. Infection induced the accumulation and activation of γδ T cells, which transiently expressed IL-17a to enhance early IL-33 production by lung epithelial cells via STAT3 phosphorylation. Subsequently, this led to type 2 immune responses with elicited infiltration of ILC2s and Tregs resulting in increased amphiregulin secretion and tissue repair. Loss of γδ T cells did not alter viral clearance or IFN-γ production. Thus, our results identify a specific requirement for γδ T cells in influenza-infected neonates by initiating type 2 immune responses, mediating tissue homeostasis, and promoting lung integrity.
Project description:Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids.
Project description:We recently found that a unique subset of innate-like γδ T cells develop from the DN2a-stage of the fetal thymus independent of the zinc-finger transcription factor B-cell leukemia/lymphoma 11b (Bcl11b). Herein we characterized these Bcl11b-independent γδ T cells in the periphery as CD5−NK1.1+ and Granzyme B+, and show that they are capable of producing interferon (IFN)-γ upon T cell receptor stimulation without Ca2+ influx. In wild-type mice, these cells were sparse in lymphoid tissues but abundant in non-lymphoid tissues such as the liver. Bcl11b-independent CD5−NK1.1+ γδ T cells appeared and contributed to early protection before Bcl11b-dependent CD5+NK1.1− γδT cells following Listeria monocytogenes infection, recapitulating their appearance during thymic development.