Transcriptional control of innate memory CD8+ T cells

CD8+ T cells are essential for host protection against intracellular pathogens and tumors. During antigen-driven responses, CD8+ T cell fate is governed by transcriptional and epigenetic processes that allow naïve CD8+ T cells to develop into a wide range of effector and conventional memory cell subsets. Over the last decades, novel techniques and major efforts led to a better understanding of the origin, nature, and short- and long-term effects of these processes on individual CD8+ T cells. Under certain conditions, naïve CD8+ T cells can acquire memory phenotype and functions in an antigen-independent manner. Although homeostatic cytokines and initial activation pathways that drive the development of these unconventional memory cells had been identified, the ensuing transcriptional profile of these cells and their degree of similarity with conventional memory cells remained ill-defined. The epigenetic events that accompany unconventional memory formation were also not known.Here, we show that innate memory cells, a type of thymic unconventional memory cells, are transcriptionally close to conventional memory cells but only partially epigenetically programmed toward the full memory fate. We also show that the sole overexpression of the transcription factor Eomesodermin (EOMES), a master regulator of effector and conventional memory cells, is able to drive many of the phenotypical, functional, transcriptional, and epigenetic features of innate memory cells, and to induce the recruitment of BRG1, a member of chromatin remodeling complexes, to innate memory gene regulatory regions. We further show that the in vivo interleukine-4-dependent development of innate memory cells is largely dependent on BRG1. We bring to light that, in innate memory cells, EOMES is recruited in many instances to genomic regions previously bound by the transcription factor RUNX3. Overall, we provide insights into the mechanisms that allow memory cell formation and T cell receptor stimulation to be uncoupled.Doctorat en Sciences médicales (Médecine)info:eu-repo/semantics/nonPublishe

Study of FibroTest and hyaluronic acid biological variation in healthy volunteers and comparison of serum hyaluronic acid biological variation between chronic liver diseases of different etiology and fibrotic stage using confidence intervals

Objectives: Personalized ranges of liver fibrosis serum biomarkers such as FibroTest or hyaluronic acid could be used for early detection of fibrotic changes in patients with progressive chronic liver disease. Our aim was to generate reliable biological variation estimates for these two biomarkers with confidence intervals for within-subject biological variation and reference change value. Design and methods: Nine fasting healthy volunteers and 66 chronic liver disease patients were included. Biological variation estimates were calculated for FibroTest in healthy volunteers, and for hyaluronic acid in healthy volunteers and chronic liver disease patients stratified by etiology and liver fibrosis stage. Results: In healthy volunteers, within-subject biological coefficient of variation (with 95% confidence intervals) and index of individuality were 20% (16%-28%) and 0.6 for FibroTest and 34% (27%-47%) and 0.79 for hyaluronic acid, respectively. Overall hyaluronic acid within-subject biological coefficient of variation was similar among non-alcoholic fatty liver disease and chronic hepatitis C with 41% (34%-52%) and 45% (39%-55%), respectively, in contrast to chronic hepatitis B with 170% (140%-215%). Hyaluronic acid within-subject biological coefficients of variation were similar between F0-F1, F2 and F3 liver fibrosis stages in non-alcoholic fatty liver disease with 34% (25%-49%), 41% (31%-59%) and 34% (23%-62%), respectively, and in chronic hepatitis C with 34% (27%-47%), 33% (26%-45%) and 38% (27%-65%), respectively. However, corresponding hyaluronic acid indexes of individuality were lower in the higher fibrosis stages. Conclusion: Non-overlapping confidence intervals of biological variation estimates allowed us to detect significant differences regarding hyaluronic acid biological variation between chronic liver disease subgroups.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

JNK1 Signaling Downstream of the EGFR Pathway Contributes to Aldara®-Induced Skin Inflammation

c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of Aldara®-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced Aldara®-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed reduced Aldara®-induced acanthosis despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced Aldara®-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

JNK1 Signaling Downstream of the EGFR Pathway Contributes to Aldara®-Induced Skin Inflammation

c-Jun N-terminal protein kinase 1 (JNK1) is involved in multiple biological processes but its implication in inflammatory skin diseases is still poorly defined. Herein, we studied the role of JNK1 in the context of Aldara®-induced skin inflammation. We observed that constitutive ablation of JNK1 reduced Aldara®-induced acanthosis and expression of inflammatory markers. Conditional deletion of JNK1 in myeloid cells led to reduced skin inflammation, a finding that was associated with impaired Aldara®-induced inflammasome activation in vitro. Next, we evaluated the specific role of JNK1 in epidermal cells. We observed reduced Aldara®-induced acanthosis despite similar levels of inflammatory markers. Transcriptomic and epigenomic analysis of keratinocytes revealed the potential involvement of JNK1 in the EGFR signaling pathway. Finally, we show that inhibition of the EGFR pathway reduced Aldara®-induced acanthosis. Taken together, these data indicate that JNK1 plays a dual role in the context of psoriasis by regulating the production of inflammatory cytokines by myeloid cells and the sensitivity of keratinocytes to EGFR ligands. These results suggest that JNK1 could represent a valuable therapeutic target in the context of psoriasis.</jats:p

P1.14 MONOCLONAL B-CELL LYMPHOCYTOSIS (MBL): RESULTS OF A ROUTINE SCREENING IN A GENERAL HOSPITAL

info:eu-repo/semantics/publishe

EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming

AbstractMemory CD8+ T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8+ T cell innate memory program.</jats:p

EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming.

Memory CD8 T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8 T cell innate memory program