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1.
Nat Immunol ; 25(2): 294-306, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38238608

ABSTRACT

Antigen-experienced CD8+ T cells form effector and central memory T cells (TEM and TCM cells, respectively); however, the mechanism(s) controlling their lineage plasticity remains incompletely understood. Here we show that the transcription cofactor Tle3 critically regulates TEM and TCM cell fates and lineage stability through dynamic redistribution in antigen-responding CD8+ T cell genome. Genetic ablation of Tle3 promoted CD8+ TCM cell formation at the expense of CD8+ TEM cells. Lineage tracing showed that Tle3-deficient CD8+ TEM cells underwent accelerated conversion into CD8+ TCM cells while retaining robust recall capacity. Tle3 acted as a coactivator for Tbet to increase chromatin opening at CD8+ TEM cell-characteristic sites and to activate CD8+ TEM cell signature gene transcription, while engaging Runx3 and Tcf1 to limit CD8+ TCM cell-characteristic molecular features. Thus, Tle3 integrated functions of multiple transcription factors to guard lineage fidelity of CD8+ TEM cells, and manipulation of Tle3 activity could favor CD8+ TCM cell production.


Subject(s)
CD8-Positive T-Lymphocytes , Memory T Cells , Transcription Factors/genetics , Cell Differentiation , Immunologic Memory/genetics
2.
Nat Immunol ; 24(10): 1698-1710, 2023 10.
Article in English | MEDLINE | ID: mdl-37592014

ABSTRACT

In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how intrinsically disordered regions affect chromatin and control cell fate is unclear. Here, we report that deletion of an intrinsically disordered region of the pioneer factor TCF-1 (termed L1) leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1-deficient cells. Mechanistically, L1 is required for activation of T cell genes and repression of GATA2-driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes, which are subject to repression as T cells develop. These data suggest that the intrinsically disordered N terminus of TCF-1 maintains T cell lineage fidelity.


Subject(s)
T-Lymphocytes , Transcription Factors , Transcription Factors/metabolism , Cell Differentiation/genetics , Cell Lineage/genetics , T-Lymphocytes/metabolism , T Cell Transcription Factor 1/genetics , Chromatin/metabolism
3.
Nat Immunol ; 23(8): 1222-1235, 2022 08.
Article in English | MEDLINE | ID: mdl-35882936

ABSTRACT

CD8+ T cell homeostasis is maintained by the cytokines IL-7 and IL-15. Here we show that transcription factors Tcf1 and Lef1 were intrinsically required for homeostatic proliferation of CD8+ T cells. Multiomics analyses showed that Tcf1 recruited the genome organizer CTCF and that homeostatic cytokines induced Tcf1-dependent CTCF redistribution in the CD8+ T cell genome. Hi-C coupled with network analyses indicated that Tcf1 and CTCF acted cooperatively to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8+ T cells before and after cytokine stimulation. Ablating CTCF phenocopied the proliferative defects caused by Tcf1 and Lef1 deficiency. Tcf1 and CTCF controlled a similar set of genes that regulated cell cycle progression and promoted CD8+ T cell homeostatic proliferation in vivo. These findings identified CTCF as a Tcf1 cofactor and uncovered an intricate interplay between Tcf1 and CTCF that modulates the genomic architecture of CD8+ T cells to preserve homeostasis.


Subject(s)
CD8-Positive T-Lymphocytes , Signal Transduction , CD8-Positive T-Lymphocytes/metabolism , Cytokines/metabolism , Genomics , Homeostasis
4.
Nat Immunol ; 23(3): 386-398, 2022 03.
Article in English | MEDLINE | ID: mdl-35190717

ABSTRACT

The mechanisms underlying the heightened protection mediated by central memory CD8+ T (TCM) cells remain unclear. Here we show that the transcription factor Tcf1 was required in resting TCM cells to generate secondary effector CD8+ T cells and to clear pathogens during recall responses. Recall stimulation of CD8+ TCM cells caused extensive reprogramming of the transcriptome and chromatin accessibility, leading to rapid induction of glycolytic enzymes, cell cycle regulators and transcriptional regulators, including Id3. This cluster of genes did not require Tcf1 in resting CD8+ TCM cells, but depended on Tcf1 for optimal induction and chromatin opening in recall-stimulated CD8+ TCM cells. Tcf1 bound extensively to these recall-induced gene loci in resting CD8+ TCM cells and mediated chromatin interactions that positioned these genes in architectural proximity with poised enhancers. Thus, Tcf1 preprogramed a transcriptional program that supported the bioenergetic and proliferative needs of CD8+ TCM cells in case of a secondary challenge.


Subject(s)
CD8-Positive T-Lymphocytes , Immunologic Memory , Animals , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/genetics , Chromatin/metabolism , Glycolysis/genetics , Immunologic Memory/genetics , Mice , Mice, Inbred C57BL
5.
Nat Immunol ; 21(8): 938-949, 2020 08.
Article in English | MEDLINE | ID: mdl-32572242

ABSTRACT

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (TRM) CD8+ T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain TRM cells. We show that peripheral infections generate antigen-specific CD8+ memory T cells in the brain that adopt a unique TRM signature. Upon depletion of circulating and perivascular memory T cells, this brain signature was enriched and the surveilling properties of brain TRM cells was revealed by intravital imaging. Notably, peripherally induced brain TRM cells showed evidence of rapid activation and enhanced cytokine production and mediated protection after brain infections. These data reveal that peripheral immunizations can generate brain TRM cells and will guide potential use of T cells as therapeutic strategies against CNS infections and neurological diseases.


Subject(s)
Brain/immunology , CD8-Positive T-Lymphocytes/immunology , Central Nervous System Infections/immunology , Immunologic Memory/immunology , Animals , Bacterial Infections/immunology , Brain/cytology , Lymphocyte Activation/immunology , Mice , Virus Diseases/immunology
6.
Nat Immunol ; 21(7): 790-801, 2020 07.
Article in English | MEDLINE | ID: mdl-32424361

ABSTRACT

Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium-induced plasmablasts but they also reveal new targets and strategies to improve anti-Plasmodium humoral immunity.


Subject(s)
Immunity, Humoral , Malaria/immunology , Plasma Cells/metabolism , Plasmodium falciparum/immunology , Adolescent , Adult , Amino Acids/administration & dosage , Amino Acids/metabolism , Animals , Antibodies, Protozoan/blood , Antibodies, Protozoan/immunology , Antibodies, Protozoan/metabolism , Antimalarials/administration & dosage , DNA, Protozoan/isolation & purification , Disease Models, Animal , Germinal Center/cytology , Germinal Center/immunology , Germinal Center/metabolism , Host-Parasite Interactions/immunology , Humans , Malaria/blood , Malaria/drug therapy , Malaria/parasitology , Mice , Mice, Transgenic , Middle Aged , Nutrients/metabolism , Plasma Cells/immunology , Plasma Cells/parasitology , Plasmodium falciparum/genetics , Plasmodium falciparum/isolation & purification , Proof of Concept Study , Young Adult
7.
Nat Immunol ; 20(9): 1150-1160, 2019 09.
Article in English | MEDLINE | ID: mdl-31358996

ABSTRACT

Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor-product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1+) early innate lymphoid progenitors (EILPs), which we named 'specified EILPs' and 'committed EILPs'. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.


Subject(s)
Cell Lineage/immunology , Dendritic Cells/cytology , Hepatocyte Nuclear Factor 1-alpha/immunology , Lymphoid Progenitor Cells/cytology , T-Lymphocytes/cytology , Animals , Cell Differentiation/immunology , Cells, Cultured , Gene Expression Regulation/genetics , Hepatocyte Nuclear Factor 1-alpha/genetics , Mice , Mice, Inbred C57BL , Transcription, Genetic/genetics
9.
Nat Immunol ; 20(3): 337-349, 2019 03.
Article in English | MEDLINE | ID: mdl-30778251

ABSTRACT

Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Neoplasms, Experimental/immunology , Proto-Oncogene Proteins c-myb/immunology , Stem Cells/immunology , Animals , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/virology , Cell Differentiation/immunology , Cell Line, Tumor , HEK293 Cells , Humans , Immunologic Memory/genetics , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/metabolism , Lymphocytic Choriomeningitis/virology , Lymphocytic choriomeningitis virus/immunology , Lymphocytic choriomeningitis virus/physiology , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/virology , Proto-Oncogene Proteins c-myb/genetics , Proto-Oncogene Proteins c-myb/metabolism , Stem Cells/metabolism , Stem Cells/virology , T Cell Transcription Factor 1/genetics , T Cell Transcription Factor 1/immunology , T Cell Transcription Factor 1/metabolism
11.
Nat Immunol ; 18(8): 931-939, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28604718

ABSTRACT

Activated CD8+ T cells differentiate into cytotoxic effector (TEFF) cells that eliminate target cells. How TEFF cell identity is established and maintained is not fully understood. We found that Runx3 deficiency limited clonal expansion and impaired upregulation of cytotoxic molecules in TEFF cells. Runx3-deficient CD8+ TEFF cells aberrantly upregulated genes characteristic of follicular helper T (TFH) cell lineage, including Bcl6, Tcf7 and Cxcr5. Mechanistically, the Runx3-CBFß transcription factor complex deployed H3K27me3 to Bcl6 and Tcf7 genes to suppress the TFH program. Ablating Tcf7 in Runx3-deficient CD8+ TEFF cells prevented the upregulation of TFH genes and ameliorated their defective induction of cytotoxic genes. As such, Runx3-mediated Tcf7 repression coordinately enforced acquisition of cytotoxic functions and protected the cytotoxic lineage integrity by preventing TFH-lineage deviation.


Subject(s)
Core Binding Factor Alpha 3 Subunit/genetics , Lymphopoiesis/genetics , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Helper-Inducer/cytology , Animals , Cell Lineage , Enzyme-Linked Immunosorbent Assay , Epigenesis, Genetic , Gene Expression Regulation , Hepatocyte Nuclear Factor 1-alpha/genetics , Immunohistochemistry , Mice , Proto-Oncogene Proteins c-bcl-6/genetics , Receptors, CXCR5/genetics , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, RNA , Up-Regulation
12.
Nat Immunol ; 17(6): 695-703, 2016 06.
Article in English | MEDLINE | ID: mdl-27111144

ABSTRACT

The CD4(+) and CD8(+) T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4(+) lineage-associated genes including Cd4, Foxp3 and Rorc in CD8(+) T cells. Tcf1- and Lef1-deficient CD8(+) T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4(+) lineage genes in CD8(+) T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Hepatocyte Nuclear Factor 1-alpha/metabolism , Histone Deacetylases/metabolism , Lymphoid Enhancer-Binding Factor 1/metabolism , Acetylation , Animals , Cell Differentiation/genetics , Cell Lineage/genetics , Cells, Cultured , Female , Gene Expression Regulation , Hepatocyte Nuclear Factor 1-alpha/genetics , Histone Deacetylases/genetics , Lymphoid Enhancer-Binding Factor 1/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation/genetics , Protein Domains/genetics
13.
Nat Immunol ; 16(9): 980-90, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26214741

ABSTRACT

Follicular helper T cells (T(FH) cells) are specialized effector CD4(+) T cells that help B cells develop germinal centers (GCs) and memory. However, the transcription factors that regulate the differentiation of T(FH) cells remain incompletely understood. Here we report that selective loss of Lef1 or Tcf7 (which encode the transcription factor LEF-1 or TCF-1, respectively) resulted in T(FH) cell defects, while deletion of both Lef1 and Tcf7 severely impaired the differentiation of T(FH) cells and the formation of GCs. Forced expression of LEF-1 enhanced T(FH) differentiation. LEF-1 and TCF-1 coordinated such differentiation by two general mechanisms. First, they established the responsiveness of naive CD4(+) T cells to T(FH) cell signals. Second, they promoted early T(FH) differentiation via the multipronged approach of sustaining expression of the cytokine receptors IL-6Rα and gp130, enhancing expression of the costimulatory receptor ICOS and promoting expression of the transcriptional repressor Bcl6.


Subject(s)
Cell Differentiation/immunology , Cytokine Receptor gp130/immunology , DNA-Binding Proteins/immunology , Germinal Center/immunology , Hepatocyte Nuclear Factor 1-alpha/immunology , Lymphoid Enhancer-Binding Factor 1/immunology , Receptors, Interleukin-6/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , B-Lymphocytes/immunology , Cell Differentiation/genetics , Cytokine Receptor gp130/genetics , DNA-Binding Proteins/genetics , Gene Expression Profiling , Gene Expression Regulation , Germinal Center/metabolism , Hepatocyte Nuclear Factor 1-alpha/genetics , Lymphoid Enhancer-Binding Factor 1/genetics , Mice , Proto-Oncogene Proteins c-bcl-6 , Receptors, Interleukin-6/genetics , T-Lymphocytes, Helper-Inducer/metabolism
14.
Nat Immunol ; 16(10): 1044-50, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26280998

ABSTRACT

The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate.


Subject(s)
Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Immunity, Innate , Lymphocytes/cytology , Lymphocytes/immunology , T Cell Transcription Factor 1/genetics , Up-Regulation , Animals , Cells, Cultured , Flow Cytometry , Mice , Microarray Analysis , T Cell Transcription Factor 1/metabolism
15.
Nat Immunol ; 15(7): 646-656, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24836425

ABSTRACT

The transcription factors TCF-1 and LEF-1 are essential for early T cell development, but their roles beyond the CD4(+)CD8(+) double-positive (DP) stage are unknown. By specific ablation of these factors in DP thymocytes, we demonstrated that deficiency in TCF-1 and LEF-1 diminished the output of CD4(+) T cells and redirected CD4(+) T cells to a CD8(+) T cell fate. The role of TCF-1 and LEF-1 in the CD4-versus-CD8 lineage 'choice' was mediated in part by direct positive regulation of the transcription factor Th-POK. Furthermore, loss of TCF-1 and LEF-1 unexpectedly caused derepression of CD4 expression in T cells committed to the CD8(+) lineage without affecting the expression of Runx transcription factors. Instead, TCF-1 physically interacted with Runx3 to cooperatively silence Cd4. Thus, TCF-1 and LEF-1 adopted distinct genetic 'wiring' to promote the CD4(+) T cell fate and establish CD8(+) T cell identity.


Subject(s)
CD4 Antigens/physiology , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Core Binding Factor Alpha 3 Subunit/physiology , Lymphoid Enhancer-Binding Factor 1/physiology , T Cell Transcription Factor 1/physiology , Transcription Factors/physiology , Animals , Cell Lineage , Female , Hepatocyte Nuclear Factor 1-alpha , Male , Mice
16.
Blood ; 143(2): 166-177, 2024 Jan 11.
Article in English | MEDLINE | ID: mdl-37871574

ABSTRACT

ABSTRACT: Persisting alloreactive donor T cells in target tissues are a determinant of graft-versus-host disease (GVHD), but the transcriptional regulators that control the persistence and function of tissue-infiltrating T cells remain elusive. We demonstrate here that Id3, a DNA-binding inhibitor, is critical for sustaining T-cell responses in GVHD target tissues in mice, including the liver and intestine. Id3 loss results in aberrantly expressed PD-1 in polyfunctional T helper 1 (Th1) cells, decreased tissue-infiltrating PD-1+ polyfunctional Th1 cell numbers, impaired maintenance of liver TCF-1+ progenitor-like T cells, and inhibition of GVHD. PD-1 blockade restores the capacity of Id3-ablated donor T cells to mediate GVHD. Single-cell RNA-sequencing analysis revealed that Id3 loss leads to significantly decreased CD28- and PI3K/AKT-signaling activity in tissue-infiltrating polyfunctional Th1 cells, an indicator of active PD-1/PD-L1 effects. Id3 is also required for protecting CD8+ T cells from the PD-1 pathway-mediated suppression during GVHD. Genome-wide RNA-sequencing analysis reveals that Id3 represses transcription factors (e.g., Nfatc2, Fos, Jun, Ets1, and Prdm1) that are critical for PD-1 transcription, exuberant effector differentiation, and interferon responses and dysfunction of activated T cells. Id3 achieves these effects by restraining the chromatin accessibility for these transcription factors. Id3 ablation in donor T cells preserved their graft vs tumor effects in mice undergoing allogeneic hematopoietic stem cell transplantation. Furthermore, CRISPR/Cas9 knockout of ID3 in human CD19-directed chimeric antigen receptor T cells retained their antitumor activity in NOD/SCID/IL2Rg-/- mice early after administration. These findings identify that ID3 is an important target to reduce GVHD, and the gene-editing program of ID3 may have broad implications in T-cell-based immunotherapy.


Subject(s)
Graft vs Host Disease , Programmed Cell Death 1 Receptor , Mice , Animals , Humans , Programmed Cell Death 1 Receptor/genetics , Phosphatidylinositol 3-Kinases , Mice, SCID , Mice, Inbred NOD , Graft vs Host Disease/prevention & control , Transcription Factors , RNA
17.
Proc Natl Acad Sci U S A ; 120(51): e2313476120, 2023 Dec 19.
Article in English | MEDLINE | ID: mdl-38085779

ABSTRACT

CD62L+ central memory CD8+ T (TCM) cells provide enhanced protection than naive cells; however, the underlying mechanism, especially the contribution of higher-order genomic organization, remains unclear. Systematic Hi-C analyses reveal that antigen-experienced CD8+ T cells undergo extensive rewiring of chromatin interactions (ChrInt), with TCM cells harboring specific interaction hubs compared with naive CD8+ T cells, as observed at cytotoxic effector genes such as Ifng and Tbx21. TCM cells also acquire de novo CTCF (CCCTC-binding factor) binding sites, which are not only strongly associated with TCM-specific hubs but also linked to increased activities of local gene promoters and enhancers. Specific ablation of CTCF in TCM cells impairs rapid induction of genes in cytotoxic program, energy supplies, transcription, and translation by recall stimulation. Therefore, acquisition of CTCF binding and ChrInt hubs by TCM cells serves as a chromatin architectural basis for their transcriptomic dynamics in primary response and for imprinting the code of "recall readiness" against secondary challenge.


Subject(s)
CD8-Positive T-Lymphocytes , Chromatin , Chromatin/genetics , CCCTC-Binding Factor/genetics , CCCTC-Binding Factor/metabolism , Binding Sites , Genomics
18.
Proc Natl Acad Sci U S A ; 120(27): e2302785120, 2023 07 04.
Article in English | MEDLINE | ID: mdl-37364124

ABSTRACT

The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (TN) and P14 circulating memory CD8 T cells (TCIRCM), with the former being more susceptible to radiation-induced numeric loss. While TN cell numbers rapidly recovered, as previously described, the number of P14 TCIRCM cells remained low at least 9 mo after radiation exposure. Additionally, the remaining P14 TCIRCM in irradiated hosts exhibited an inefficient transition to a central memory (CD62L+) phenotype compared to nonirradiated P14 chimeras. WBI also resulted in long-lasting T cell intrinsic deficits in memory CD8 T cells, including diminished cytokine and chemokine production along with impaired secondary expansion upon cognate Ag reencounter. Irradiated P14 chimeras displayed significantly higher bacterial burden after challenge with Listeria monocytogenes expressing the LCMV GP33-41 epitope relative to nonirradiated controls, likely due to radiation-induced numerical and functional impairments. Taken together, our findings suggest that sublethal radiation exposure caused a long-term numerical, impaired differentiation, and functional dysregulation in preexisting TCIRCM, rendering previously protected hosts susceptible to reinfection.


Subject(s)
Lymphocytic Choriomeningitis , Whole-Body Irradiation , Mice , Animals , Neoplasm Recurrence, Local , CD8-Positive T-Lymphocytes , Lymphocytic choriomeningitis virus , Immunologic Memory , Mice, Inbred C57BL
19.
Immunity ; 45(6): 1341-1354, 2016 12 20.
Article in English | MEDLINE | ID: mdl-27986453

ABSTRACT

Differentiation of effector and memory CD8+ T cells is accompanied by extensive changes in the transcriptome and histone modifications at gene promoters; however, the enhancer repertoire and associated gene regulatory networks are poorly defined. Using histone mark chromatin immunoprecipitation coupled with deep sequencing, we mapped the enhancer and super-enhancer landscapes in antigen-specific naive, differentiated effector, and central memory CD8+ T cells during LCMV infection. Epigenomics-based annotation revealed a highly dynamic repertoire of enhancers, which were inherited, de novo activated, decommissioned and re-activated during CD8+ T cell responses. We employed a computational algorithm to pair enhancers with target gene promoters. On average, each enhancer targeted three promoters and each promoter was regulated by two enhancers. By identifying enriched transcription factor motifs in enhancers, we defined transcriptional regulatory circuitry at each CD8+ T cell response stage. These multi-dimensional datasets provide a blueprint for delineating molecular mechanisms underlying functional differentiation of CD8+ T cells.


Subject(s)
Arenaviridae Infections/immunology , CD8-Positive T-Lymphocytes/immunology , Enhancer Elements, Genetic/immunology , Gene Expression Regulation/immunology , Lymphocyte Activation/immunology , Algorithms , Animals , Cell Differentiation/genetics , Cell Differentiation/immunology , Chromatin Immunoprecipitation , Computational Biology/methods , Disease Models, Animal , Enhancer Elements, Genetic/genetics , Epigenomics/methods , Gene Regulatory Networks , High-Throughput Nucleotide Sequencing , Lymphocyte Activation/genetics , Lymphocytic choriomeningitis virus , Mice , Promoter Regions, Genetic/genetics , Promoter Regions, Genetic/immunology
20.
Nat Immunol ; 18(9): 957-958, 2017 08 22.
Article in English | MEDLINE | ID: mdl-28829449
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