Similar Datasets
Project description:Chronic infection with cytomegalovirus (CMV) leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to be mainly determined by the availability of antigenic stimuli during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that T cell fate decisions, taken during the acute phase of murine CMV infection, can alter the level of memory inflation by more than 1000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial clonal expansion. Instead, those rare T cell families that strongly dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem cell-like source for the antigen-driven maintenance of memory inflation.
2020-09-09 | GSE157641 | GEO
Project description:Chronic infection with cytomegalovirus (CMV) leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to be mainly determined by the availability of antigenic stimuli during the chronic phase of infection. However, by mapping the long-term development of CD8+ T cell families derived from single naive precursors, we find that T cell fate decisions, taken during the acute phase of murine CMV infection, can alter the level of memory inflation by more than 1000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial clonal expansion. Instead, those rare T cell families that strongly dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem cell-like source for the antigen-driven maintenance of memory inflation.
2020-09-05 | GSE157501 | GEO
Project description:Early emergence of T central memory precursors programs clonal dominance during chronic viral infection
| PRJNA662315 | ENA
Project description:Early emergence of T central memory precursors programs clonal dominance during chronic viral infection [scRNAseq]
| PRJNA661528 | ENA
Project description:Early emergence of T central memory precursors programs clonal dominance during chronic viral infection [bulkRNAseq]
| PRJNA662319 | ENA
Project description:Both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) establish persistent infections that induce the accumulation of virus-specific T cells over time in a process called memory inflation. It has been proposed that T cells expressing T-cell receptors (TCRs) with high affinity for HCMV-derived peptides are preferentially selected after acute HCMV infection. To test this in the murine model, small numbers of OT-I transgenic T cells, which express a TCR with high affinity for the SIINFEKL peptide, were transferred into congenic mice and recipients were challenged with recombinant MCMV expressing SIINFEKL. OT-I T cells were selectively enriched during the first 3 weeks of infection. Similarly, in the absence of OT-I T cells, the functional avidity of SIINFEKL-specific T cells increased from early to late times postinfection. However, even when exceedingly small numbers of OT-I T cells were transferred, their inflation limited the inflation of host-derived T cells specific for SIINFEKL. Importantly, subtle minor histocompatibility differences led to late rejection of the transferred OT-I T cells in some mice, which allowed host-derived T cells to inflate substantially. Thus, T cells with a high functional avidity are selected shortly after MCMV infection and continuously sustain their clonal dominance in a competitive manner.
| S-EPMC4500790 | biostudies-literature
Project description:Experimental and computational studies have revealed that T-cell cross-reactivity is a widespread phenomenon that can either be advantageous or detrimental to the host. In particular, detrimental effects can occur whenever the clonal dominance of memory cells is not justified by their infection-clearing capacity. Using an agent-based model of the immune system, we recently predicted the "memory anti-naïve" phenomenon, which occurs when the secondary challenge is similar but not identical to the primary stimulation. In this case, the pre-existing memory cells formed during the primary infection may be rapidly deployed in spite of their low affinity and can actually prevent a potentially higher affinity naïve response from emerging, resulting in impaired viral clearance. This finding allowed us to propose a mechanistic explanation for the concept of "antigenic sin" originally described in the context of the humoral response. However, the fact that antigenic sin is a relatively rare occurrence suggests the existence of evolutionary mechanisms that can mitigate the effect of the memory anti-naïve phenomenon. In this study we use computer modeling to further elucidate clonal dominance and the memory anti-naïve phenomenon, and to investigate a possible mitigating factor called attrition. Attrition has been described in the experimental and computational literature as a combination of competition for space and apoptosis of lymphocytes via type-I interferon in the early stages of a viral infection. This study systematically explores the relationship between clonal dominance and the mechanism of attrition. Our results suggest that attrition can indeed mitigate the memory anti-naïve effect by enabling the emergence of a diverse, higher affinity naïve response against the secondary challenge. In conclusion, modeling attrition allows us to shed light on the nature of clonal interaction and dominance.
| S-EPMC6626922 | biostudies-literature
Project description:T large granular lymphocyte leukemia (T-LGLL) is a clonal lymphoproliferative disorder that can arise in the context of pathologic or physiologic cytotoxic T-cell (CTL) responses. STAT3 mutations are often absent in typical T-LGLL, suggesting that in a significant fraction of patients, antigen-driven expansion alone can maintain LGL clone persistence. We set out to determine the relationship between activating STAT3 hits and CTL clonal selection at presentation and in response to therapy. Thus, a group of patients with T-LGLL were serially subjected to deep next-generation sequencing (NGS) of the T-cell receptor (TCR) Vβ complementarity-determining region 3 (CDR3) and STAT3 to recapitulate clonal hierarchy and dynamics. The results of this complex analysis demonstrate that STAT3 mutations produce either a sweeping or linear subclone within a monoclonal CTL population either early or during the course of disease. Therapy can extinguish a LGL clone, silence it, or adapt mechanisms to escape elimination. LGL clones can persist on elimination of STAT3 subclones, and alternate STAT3-negative CTL clones can replace therapy-sensitive CTL clones. LGL clones can evolve and are fueled by a nonextinguished antigenic drive. STAT3 mutations can accelerate this process or render CTL clones semiautonomous and not reliant on physiologic stimulation.
| S-EPMC6436009 | biostudies-literature
Project description:The circulating precursor cells that give rise to human resident memory T cells (TRM) are poorly characterized. We used an in vitro differentiation system and human skin-grafted mice to study TRM generation from circulating human memory T cell subsets. In vitro TRM differentiation was associated with functional changes, including enhanced IL-17A production and FOXP3 expression in CD4+ T cells and granzyme B production in CD8+ T cells, changes that mirrored the phenotype of T cells in healthy human skin. Effector memory T cells (TEM) had the highest conversion rate to TRM in vitro and in vivo, but central memory T cells (TCM) persisted longer in the circulation, entered the skin in larger numbers, and generated increased numbers of TRM. In summary, TCM are highly efficient precursors of human skin TRM, a feature that may underlie their known association with effective long-term immunity.
| S-EPMC9435065 | biostudies-literature
Project description:Cooperation and division of labour are fundamental in the 'major transitions' in evolution. While the factors regulating cell differentiation in multi-cellular organisms are quite well understood, we are just beginning to unveil the mechanisms underlying individual specialization in cooperative groups of animals. Clonal ants allow the study of which factors influence task allocation without confounding variation in genotype and morphology. Here, we subjected larvae and freshly hatched workers of the clonal ant Platythyrea punctata to different rearing conditions and investigated how these manipulations affected division of labour among pairs of oppositely treated, same-aged clonemates. High rearing temperature, physical stress, injury and malnutrition increased the propensity of individuals to become subordinate foragers rather than dominant reproductives. This is reflected in changed gene regulation: early stages of division of labour were associated with different expression of genes involved in nutrient signalling pathways, metabolism and the phenotypic response to environmental stimuli. Many of these genes appear to be capable of responding to a broad range of stressors. They might link environmental stimuli to behavioural and phenotypic changes and could therefore be more broadly involved in caste differentiation in social insects. Our experiments also shed light on the causes of behavioural variation among genetically identical individuals.
| S-EPMC6125893 | biostudies-literature