Project description:This data is from a murine model established to study the lasting impact of allergic airway sensitization on subsequent anti-viral memory T cell responses and the ability to develop protective immunity to reinfection. Animals were either sensitised by exposure to HDM or PBS and then subsequently exposed to influenza virus. Samples were collected at various time points for analysis of both CD8 and C4 positive tissue resident memory T cells.
Project description:Memory T cells provide immunity against pathogen reinvasion, but mechanisms of their long-term maintenance is unclear. Here we show that mice with the deletion of the transcription factor Foxo1 in activated CD8+ T cells had defective secondary but not primary responses to Listeria monocytogenes infection. Compared to short-lived effector T cells, memory precursor effector T cells expressed higher amounts of Foxo1 that promoted their generation and maintenance. Gene expression profiling and chromatin immunoprecipitation sequencing experiments revealed the chemokine receptor CCR7 and the transcription factor TCF1 as novel Foxo1-bound target genes with critical functions in memory T cell trafficking and transcriptional regulation. These findings demonstrate that Foxo1 is selectively incorporated into the genetic program that regulates memory but not effector CD8+ T cell responses to infection. CD8+ T cells were isolated from wild-type or Foxo1tagBirA mice in which Foxo1 is endogenously biotinylated. Foxo1 binding targets in CD8+ cells were identified by using Foxo1 antibody- and Streptavidin- ChIP-Seq approaches.
Project description:CD8 tissue-resident memory T cells (TRM) provide frontline immunity in mucosal tissues. The mechanisms regulating CD8 TRM maintenance, heterogeneity, protective and pathological functions are largely elusive. Here we identify an epitope-specific CD8 TRM population that is maintained by in situ MHC-I and B7 signaling following acute influenza infection. These TRM cells co-exhibit exhausted-like phenotypes and memory features, and provide heterologous immunity against secondary infection. PD-L1 blockade at the memory stage promotes exhausted-like TRM rejuvenation and secondary immunity at the cost of developing post-infection fibrotic sequelae. Increased numbers of CD8 TRM cells are observed in the lungs of pulmonary fibrosis patients compared to control patients. Thus, TRM exhaustion results from a tissue-specific cellular adaptation to balance fibrotic sequelae and secondary immunity.
Project description:The transcription factor (TF) networks that regulate the differentiation of resident versus circulating memory CD8+ T cells are incompletely understood. Here we show that the TF Bcl11b restricts gut resident memory (Trm) cell differentiation, while promoting splenic T central memory (Tcm) and effector memory (Tem) cell differentiation. The reduction of Bcl11b-deficient splenic Tcm and Tem cells was not due to major alterations in their programs, but rather due to the increased homing of their precursors to the small intestine. However, Bcl11b-deficient resident memory precursor cells upregulated residency program, including the TFs Ahr and Prdm1 (encoding Blimp1), and downregulated Tcf7, which restricts the residency program and promotes tissue egress. Bcl11b directly bound at Ahr and Prdm1, as well as at Tcf7 genes. Abrogating Ahr and Prdm1, or restoration of Tcf7 expression in Bcl11b-deficient cells led to partial correction of the excessive resident memory cell differentiation. Functionally, Bcl11b-deficient memory CD8+ T cells had an impaired recall response, but anti-tumor immunity was increased in adoptive cell therapy. Bcl11b also repressed the residency program in human CD8+ T cells and human Bcl11b low tumor-infiltrating lymphocytes showed increased residency gene expression. Thus, Bcl11b plays a critical role in balancing the circulating and tissue residency programs and reveals a potential novel target for cancer immunotherapies.
Project description:The transcription factor (TF) networks that regulate the differentiation of resident versus circulating memory CD8+ T cells are incompletely understood. Here we show that the TF Bcl11b restricts gut resident memory (Trm) cell differentiation, while promoting splenic T central memory (Tcm) and effector memory (Tem) cell differentiation. The reduction of Bcl11b-deficient splenic Tcm and Tem cells was not due to major alterations in their programs, but rather due to the increased homing of their precursors to the small intestine. However, Bcl11b-deficient resident memory precursor cells upregulated residency program, including the TFs Ahr and Prdm1 (encoding Blimp1), and downregulated Tcf7, which restricts the residency program and promotes tissue egress. Bcl11b directly bound at Ahr and Prdm1, as well as at Tcf7 genes. Abrogating Ahr and Prdm1, or restoration of Tcf7 expression in Bcl11b-deficient cells led to partial correction of the excessive resident memory cell differentiation. Functionally, Bcl11b-deficient memory CD8+ T cells had an impaired recall response, but anti-tumor immunity was increased in adoptive cell therapy. Bcl11b also repressed the residency program in human CD8+ T cells and human Bcl11b low tumor-infiltrating lymphocytes showed increased residency gene expression. Thus, Bcl11b plays a critical role in balancing the circulating and tissue residency programs and reveals a potential novel target for cancer immunotherapies.
Project description:Adoptive T cell therapies hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Using mice lacking von Hippel Lindau (VHL) in CD8+ T cells and RNA-sequencing (RNA-seq), we identified tissue-resident memory (TRM)-like TIL in mouse models of malignancy. Additionally, we found that VHL-deficient TIL exhibited a core TRM signature despite an exhaustion-associated phenotype. These results reveal a key role for VHL/HIF axis in controlling the formation of a TRM CD8+ T cell subset in primary and secondary tumors that resists functional exhaustion and mediates strong anti-tumor responses.
Project description:A primary immune response is typically initiated in secondary lymphoid organs. Virtual memory CD8+ T (TVM) cells are antigen-inexperienced T cells of a central-memory phenotype, acquired through self antigen-driven homeostatic proliferation. Unexpectedly, here we find that, TVM cells are composed of CCR2+ and CCR2- subsets that differentially elaborate a spectrum of effector- and memory-poised functions directly in the tissue. During a primary flu infection, TVM cells rapidly infiltrate the lung in the first day and execute early viral control. TVM cells that recognize viral antigen are retained in the tissue, clonally expand independent of secondary lymphoid organs, and preferentially give rise to tissue-resident memory cells. By orchestrating an extra-lymphoid primary response, heterogenous TVM cells bridge innate reaction and adaptive memory directly in the infected tissue.