T cell factor-1 (TCF-1), encoded by Tcf7, is a transcription factor and histone deacetylase (HDAC) essential for commitment to both the T cell and the innate lymphoid cell (ILC) lineages in mammals. ...In this review, we discuss the multifunctional role of TCF-1 in establishing these lineages and the requirement for TCF-1 throughout lineage differentiation and maintenance of lineage stability. We highlight recent reports showing promise for TCF-1 as a novel biomarker to identify recently characterized subsets of exhausted CD8+ T cells that may help to predict patient responses to immune checkpoint blockade (ICB).
T cell factor-1 (TCF-1) acts as a transcription factor and histone deacetylase (HDAC) in both mouse and humans to shape innate and adaptive immunity.Expression of TCF-1 is necessary for the development of ILC progenitor cells in mouse bone marrow.In murine T cell development, TCF-1 is critical for ETP development, commitment to the CD4+ T cell lineage, and stabilization of CD8+ T cells by suppressing alternative fate differentiation.Increased TCF-1 expression is important for the development of central memory CD8+ T cells that provide long-term protection following acute viral infection in mice.TCF-1 is critical for the development of Tex-stem cells that replenish Tex-term cells following chronic viral infection and in response to tumor formation. The presence of Tex-stem cells can be predictive of good prognosis in various cancer types and help to mediate patient responses to ICB.
Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed ...that CD8+CD103+ Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8+CD103+ Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8+CD103+ Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8+CD103+ Trm cell development and survival.
•CD8+CD103+ Trm cells protect against infection in the absence of circulating memory•T-box transcription factor downregulation drives CD8+CD103+ Trm cell development•TGF-β and the T-box transcription factors show reciprocal downregulation•Residual T-bet expression is required for IL-15-mediated CD8+CD103+ Trm cell survival
Molecular events that regulate Trm cell formation remain poorly defined. Mackay and colleagues demonstrate that a complex interplay between Eomes and T-bet underpins CD8+CD103+ Trm cell formation. Although both T-box transcription factors must be downregulated, Eomes must be completely extinguished, whereas residual T-bet expression is essential for IL-15-mediated long-term survival.
Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by ...suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.
Various microbial metabolites promote cell transformation. In this issue of Immunity, Cong et al. show that deoxycholic acid (DCA), a microbial metabolite of bile, promotes tumor growth by suppressing antitumor CD8+ T cell responses via dysregulation of calcium efflux.
Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 ...aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ. In this context, NLRP1, IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.
Innate lymphoid cell (ILC) populations protect against infection and are essential for lymphoid tissue formation and tissue remodeling after damage. Nfil3 is implicated in the function of adaptive ...immune lineages and NK cell development, but it is not yet known if Nfil3 regulates other innate lymphoid lineages. Here, we identify that Nfil3 is essential for the development of Peyer's patches and ILC2 and ILC3 subsets. Loss of Nfil3 selectively reduced Peyer's patch formation and was accompanied by impaired recruitment and distribution of lymphocytes within the patches. ILC subsets exhibited high Nfil3 expression and genetic deletion of Nfil3 severely compromised the development of all subsets. Subsequently, Nfil3(-/-) mice were highly susceptible to disease when challenged with inflammatory or infectious agents. Thus, we demonstrate that Nfil3 is a key regulator of the development of ILC subsets essential for immune protection in the lung and gut.
Innate lymphoid cells (ILCs) are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors ...for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. We used global transcriptional mapping to analyze gene expression in different ILC progenitors. We identified PD-1 to be specifically expressed in PLZF+ ILCp and revealed that the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. Importantly, induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.
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•ILCp transcriptomics define the blueprint for hierarchical ILC development•PD-1 identifies the PLZF-expressing ILC precursor in the bone marrow•Transient NFIL3 expression prior to ID2 expression is required for ILC development•ID2 and TCF-1 are required to extinguish stem cell and B and T cell gene programs
Seillet et al. define the hierarchical blueprint for ILC development using global transcriptomic analyses of ILC progenitors. This revealed that PD-1 is a key marker of ILCp and uncovered a regulatory circuit governed by NFIL3 in regulating ID2 and TCF-1 essential for ILC differentiation.
In two elegant studies, Tyler Jacks’ group and colleagues unveil crucial interactions between dendritic cells and TCF1+CD8+ progenitor T cells, shaping their heterogeneity and offering potential to ...design new putative cancer immunotherapies and vaccines.
T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to ...determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8
effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.
Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack ...the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.
The 10x Genomics Chromium single-cell RNA sequencing technology is a powerful gene expression profiling platform, which is capable of profiling expression of thousands of genes in tens of thousands ...of cells simultaneously. This platform can produce hundreds of million reads in a single experiment, making it a very challenging task to quantify expression of genes in individual cells due to the massive data volume. Here we present cellCounts, a new tool for efficient and accurate quantification of Chromium data. cellCounts employs the seed-and-vote strategy to align reads to a reference genome, collapses reads to UMIs (Unique Molecular Identifiers) and then assigns UMIs to genes based on the featureCounts program. Using both simulation and real datasets for evaluation, cellCounts was found to compare favorably to cellRanger and STARsolo. cellCounts is implemented in R, making it easily integrated with other R programs for analysing Chromium data.
cellCounts was implemented as a function in R package Rsubread that can be downloaded from http://bioconductor.org/packages/release/bioc/html/Rsubread.html.
Data and analysis code used in this study can be freely accessed via La Trobe University's Institutional Repository at https://doi.org/10.26181/21588276.
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