Dataset Information

Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy.

ABSTRACT: While much of cancer immunology research has focused on anti-tumor immunity both systemically and within the tumor microenvironment, little is known about the impact of pre-existing malignancy on pathogen-specific immune responses. Here, we sought to characterize the antigen-specific CD8+ T cell response following a bacterial infection in the setting of pre-existing pancreatic adenocarcinoma. Mice with established subcutaneous pancreatic adenocarcinomas were infected with Listeria monocytogenes, and antigen-specific CD8+ T cell responses were compared to those in control mice without cancer. While the kinetics and magnitude of antigen-specific CD8+ T cell expansion and accumulation was comparable between the cancer and non-cancer groups, bacterial antigen-specific CD8+ T cells and total CD4+ and CD8+ T cells in cancer mice exhibited increased expression of the coinhibitory receptors BTLA, PD-1, and 2B4. Furthermore, increased inhibitory receptor expression was associated with reduced IFN-? and increased IL-2 production by bacterial antigen-specific CD8+ T cells in the cancer group. Taken together, these data suggest that cancer's immune suppressive effects are not limited to the tumor microenvironment, but that pre-existing malignancy induces phenotypic exhaustion in T cells by increasing expression of coinhibitory receptors and may impair pathogen-specific CD8+ T cell functionality and differentiation.

SUBMITTER: Mittal R

PROVIDER: S-EPMC4010417 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy.

Mittal Rohit R Wagener Maylene M Breed Elise R ER Liang Zhe Z Yoseph Benyam P BP Burd Eileen M EM Farris Alton B AB Coopersmith Craig M CM Ford Mandy L ML

PloS one 20140505 5

While much of cancer immunology research has focused on anti-tumor immunity both systemically and within the tumor microenvironment, little is known about the impact of pre-existing malignancy on pathogen-specific immune responses. Here, we sought to characterize the antigen-specific CD8+ T cell response following a bacterial infection in the setting of pre-existing pancreatic adenocarcinoma. Mice with established subcutaneous pancreatic adenocarcinomas were infected with Listeria monocytogenes, ...[more]

PMID: 24796533

Similar Datasets

Project description:The presence of pre-existing malignancy in murine hosts results in increased immune dysregulation and risk of mortality following a septic insult. Based on the known systemic immunologic changes that occur in cancer hosts, we hypothesized that the presence of pre-existing malignancy would result in phenotypic and functional changes in CD4+ T cell responses following sepsis. In order to conduct a non-biased, unsupervised analysis of phenotypic differences between CD4+ T cell compartments, cohorts of mice were injected with LLC1 tumor cells and tumors were allowed to grow for 3 weeks. These cancer hosts and age-matched non-cancer controls were then subjected to CLP. Splenocytes were harvested at 24h post CLP and flow cytometry and SPADE (Spanning-tree Progression Analysis of Density-normalized Events) were used to analyze populations of CD4+ cells most different between the two groups. Results indicated that relative to non-cancer controls, cancer mice contained more resting memory CD4+ T cells, more activated CD4+ effectors, and fewer naïve CD4+ T cells during sepsis, suggesting that the CD4+ T cell compartment in cancer septic hosts is one of increased activation and differentiation. Moreover, cancer septic animals exhibited expansion of two distinct subsets of CD4+ T cells relative to previously healthy septic controls. Specifically, we identified increases in both a PD-1hi population and a distinct 2B4hi BTLAhi LAG-3hi population in cancer septic animals. By combining phenotypic analysis of exhaustion markers with functional analysis of cytokine production, we found that PD-1+ CD4+ cells in cancer hosts failed to make any cytokines following CLP, while the 2B4+ PD-1lo cells in cancer mice secreted increased TNF during sepsis. In sum, the immunophenotypic landscape of cancer septic animals is characterized by both increased CD4+ T cell activation and exhaustion, findings that may underlie the observed increased mortality in mice with pre-existing malignancy following sepsis.

Project description:Congenital cytomegalovirus (cCMV) is the leading infectious cause of neurologic defects in newborns with particularly severe sequelae in the setting of primary CMV infection in the first trimester of pregnancy. The majority of cCMV cases worldwide occur after non-primary infection in CMV-seropositive women; yet the extent to which pre-existing natural CMV-specific immunity protects against CMV reinfection or reactivation during pregnancy remains ill-defined. We previously reported on a novel nonhuman primate model of cCMV in rhesus macaques where 100% placental transmission and 83% fetal loss were seen in CD4+ T lymphocyte-depleted rhesus CMV (RhCMV)-seronegative dams after primary RhCMV infection. To investigate the protective effect of preconception maternal immunity, we performed reinfection studies in CD4+ T lymphocyte-depleted RhCMV-seropositive dams inoculated in late first / early second trimester gestation with RhCMV strains 180.92 (n = 2), or RhCMV UCD52 and FL-RhCMVΔRh13.1/SIVgag, a wild-type-like RhCMV clone with SIVgag inserted as an immunological marker, administered separately (n = 3). An early transient increase in circulating monocytes followed by boosting of the pre-existing RhCMV-specific CD8+ T lymphocyte and antibody response was observed in the reinfected dams but not in control CD4+ T lymphocyte-depleted dams. Emergence of SIV Gag-specific CD8+ T lymphocyte responses in macaques inoculated with the FL-RhCMVΔRh13.1/SIVgag virus confirmed reinfection. Placental transmission was detected in only one of five reinfected dams and there were no adverse fetal sequelae. Viral whole genome, short-read, deep sequencing analysis confirmed transmission of both reinfection RhCMV strains across the placenta with ~30% corresponding to FL-RhCMVΔRh13.1/SIVgag and ~70% to RhCMV UCD52, consistent with the mixed human CMV infections reported in infants with cCMV. Our data showing reduced placental transmission and absence of fetal loss after non-primary as opposed to primary infection in CD4+ T lymphocyte-depleted dams indicates that preconception maternal CMV-specific CD8+ T lymphocyte and/or humoral immunity can protect against cCMV infection.

Project description:The contributions of commensal fungi to human health and disease are not well understood. Candida species such as C. albicans and C. glabrata are opportunistic pathogenic fungi and common colonizers of the human intestinal tract. They have been shown to affect the host immune system and interact with the gut microbiome and pathogenic microorganisms. Therefore, Candida species could be expected to play important ecological roles in the host gastrointestinal tract. Previously, our group demonstrated that pre-colonization of mice with C. albicans protected them against lethal C. difficile infection (CDI). Here, we show that mice pre-colonized with C. glabrata succumbed to CDI more rapidly than mice that were not pre-colonized suggesting an enhancement in C. difficile pathogenesis. Further, when C. difficile was added to pre-formed C. glabrata biofilms, an increase in matrix and overall biomass was observed. These effects were also shown with C. glabrata clinical isolates. Interestingly, the presence of C. difficile increased C. glabrata biofilm susceptibility to caspofungin, indicating potential effects on the fungal cell wall. Defining this intricate and intimate relationship will lead to an understanding of the role of Candida species in the context of CDI and novel aspects of Candida biology. IMPORTANCE Most microbiome studies have only considered the bacterial populations while ignoring other members of the microbiome such as fungi, other eukaryotic microorganisms, and viruses. Therefore, the role of fungi in human health and disease has been significantly understudied compared to their bacterial counterparts. This has generated a significant gap in knowledge that has negatively impacted disease diagnosis, understanding, and the development of therapeutics. With the development of novel technologies, we now have an understanding of mycobiome composition, but we do not understand the roles of fungi in the host. Here, we present findings showing that Candida glabrata, an opportunistic pathogenic yeast that colonizes the mammalian gastrointestinal tract, can impact the severity and outcome of a Clostridioides difficile infection (CDI) in a murine model. These findings bring attention to fungal colonizers during CDI, a bacterial infection of the gastrointestinal tract.

Dataset Information

Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy.

Publications

Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets