Project description:Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.
Project description:Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. To explore new pathways for reinvigoration of anti-tumor immune functions, we developed a human ex vivo exhaustion model by repetitive antigenic stimulation of primary CD8 T cells. This results in T cells that resemble patient-derived T cells in tumors on a phenotypic and transcriptional level.
Project description:To characterize the primary and recall responses to EV71 vaccines, PBMC from 19 recipients before and after vaccination with EV71 vaccine are collected and their gene expression signatures after stimulation with EV71 antigen were compared. Four-condition experiment,pre-vaccination PBMCs (stimulation vs. no stimulation with EV71 antigen) vs. post-vaccination PBMCs (stimulation vs. no stimulation with EV71 antigen)
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
Project description:Chronic hepatitis C virus (HCV) infection is associated with CD8+ T-cell exhaustion characterized by limited effector functions and thus compromised anti-viral activity. Exhausted HCV-specific CD8+ T cells are comprised of memory-like and terminally exhausted CD8+ T-cell subsets. So far, little is not known about the molecular profile and fate of these cells after elimination of chronic antigen stimulation by direct acting antiviral therapy (DAA). Here, we report an antigen-driven molecular core signature underlying exhausted CD8+ T-cell subset heterogeneity in chronic viral infection with a progenitor/progeny relationship of memory-like and terminally exhausted HCV-specific CD8+ T cells via an intermediate stage. Furthermore, transcriptional profiling reveals that the memory-like cells remain after DAA-mediated cure while terminally exhausted HCV-specific CD8+ T-cell subsets are lost. Thus, the memory polarization of the overall HCV-specific CD8+ T-cell response after cure does not result from re-differentiation of exhausted T cells. Consequently, antigen elimination has little impact on the exhausted core signature of memory-like CD8+ T cells that remains clearly different from bona fide T-cell memory. These results identify a molecular signature of T-cell exhaustion that is imprinted like a chronic scar in HCV-specific CD8+ T cells even after HCV cure, highlighting the requirement of re-programming to elicit full effector potential of exhausted T cells.
Project description:CTL exhaustion is driven by chronic antigen stimulation and is characterized by specific molecular, phenotypic and functional changes. Reversing CTLs exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. However, the therapeutic effects of ICB varies among patients and cancer types. Ibrutinib, a potent BTK inhibitor, is reported that it improved T cell function in ibrutinib long-term treated chronic lymphocytic leukemia patients. However, the mechanism remains unclear. We hypothesized ibrutinib can directly act on CD8+ T cells and reinvigorates exhausted CTLs. To test this, we generated in vitro exhausted OT-I cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with SIINFEKL peptide. We tested the effect of ibrutinib on inhibitory receptor, exhaustion-related transcription factor expression and cytokine (IFNγ, TNFα and IL-2) production. We found that ibrutinib decreased the expression of multiple inhibitory receptors on in vitro exhausted CTL while the critical transcription factor, Tox was downregulated. The cytokine production of exhausted cells was partially improved after ibrutinib treatment. Importantly, using btk deficient mice we found the effect of ibrutinib was independent of BTK expression. To conclude, these findings suggest that ibrutinib reduces CTL exhaustion. Our study provides evidence for ibrutinib’s synergistic use with cancer immunotherapy.