Similar Datasets
Project description:The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.
| S-EPMC8589447 | biostudies-literature
Project description:Sepsis, an amplified immune response to systemic infection, is characterized by a transient cytokine storm followed by chronic immune dysfunction. Consequently, sepsis survivors are highly susceptible to newly introduced infections, suggesting sepsis can influence the function and composition of the naïve CD8 T cell pool and resulting pathogen-induced primary CD8 T cell responses. Here, we explored the extent to which sepsis induces phenotypic and functional changes within the naïve CD8 T cell pool. To interrogate this, the cecal ligation and puncture (CLP) mouse model of polymicrobial sepsis was used. In normal, non-septic mice, we show type-I interferon (IFN I)-mediated signaling plays an important role in driving the phenotypic and functional heterogeneity in the naïve CD8 T cell compartment leading to increased representation of Ly6C+ naïve CD8 T cells. In response to viral infection after sepsis resolution, naïve Ly6C+ CD8 T cells generated more primary effector and memory CD8 T cells with slower conversion to a central memory CD8 T cell phenotype (Tcm) than Ly6C- naïve CD8 T cells. Importantly, as a potent inducer of cytokine storm and IFN I production, sepsis leads to increased representation of Ly6C+ naïve CD8 T cells that maintained their heightened ability to respond (i.e., effector and memory CD8 T cell accumulation and cytokine production) to primary LCMV infection. Lastly, longitudinal analyses of peripheral blood samples obtained from septic patients revealed profound changes in CD8 T cell subset composition and frequency compared to healthy controls. Thus, sepsis has the capacity to alter the composition of naïve CD8 T cells, directly influencing primary CD8 T cell responses to newly introduced infections.
| S-EPMC10597476 | biostudies-literature
Project description:Determine genome-wide open chromatin in P14 memory CD8 T cells 30 days after septic insult
2021-10-14 | GSE174358 | GEO
Project description:Determine genome-wide open chromatin in P14 memory CD8 T cells 30 days after septic insult
2021-10-14 | GSE174357 | GEO
Project description:Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells
| PRJNA729497 | ENA
Project description:Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells (RNA-Seq)
| PRJNA729503 | ENA
Project description:Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells (ATAC-Seq)
| PRJNA729502 | ENA
Project description:Long-lasting sepsis-induced immunoparalysis has been principally studied in primary (1°) memory CD8 T cells; however, the impact of sepsis on memory CD8 T cells with a history of repeated cognate Ag encounters is largely unknown but important in understanding the role of sepsis in shaping the pre-existing memory CD8 T cell compartment. Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1° and higher-order (quaternary [4°]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1° and 4° memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127/CD122), and responsiveness to homeostatic cytokines, 1° memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7/anti-IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1° memory T cells, whereas recovery of 4° memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors.
| S-EPMC9840817 | biostudies-literature
Project description:While the need for CD4 T cells in the generation of CD8 T cell memory has been well documented, the mechanism underlying their requirement remains unknown. Here, we detail an immunization method capable of generating CD8 memory T cells that are indifferent to CD4 T cell help. Using a subunit vaccination that combines polyIC and an agonistic CD40 antibody, we program protective CD4-independent CD8 T cell memory. When cells generated by combined polyIC/CD40 immunization are compared to cells produced following a CD4-dependent vaccination, Listeria monocytogenes, they display dramatic differences, both phenotypically and functionally. The memory cells generated in a CD4-deficient host by polyIC/CD40 immunization provide protection against secondary infectious challenge, whereas cells generated by LM immunization in the same environment do not. Interestingly, combined polyIC/CD40 immunization generates long-term memory cells with low Blimp-1 and elevated Eomes expression despite high expression of Blimp-1 during the primary response. The potency of combined polyIC/CD40 to elicit CD8+ T cell memory in the absence of CD4 T cells suggests that it could be considered as a vaccine adjuvant in clinical situations where CD4 responses/numbers are compromised.
| S-EPMC3922058 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-04-30 | E-GEOD-27139 | biostudies-arrayexpress