T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

Implementing the aSSKINg Pressure Injury Prevention Bundle with Palliative Homecare Patients in Kerala, India

Background: Pressure injuries and wound deterioration frequently affect homecare patients. In a palliative care non-profit in Kerala, India who provides home care services, pressure injuries are a problem for their patients despite quality person-centered care. Objective/Aims: The project objective was to implement the NHS aSSKINg bundle in the organization to prevent pressure injuries. Aim one was to create an organizational policy addressing the aSSKINg bundle. Aim two was to reduce pressure injury prevalence and incidence, with no new pressure injuries development. Aim three was to increase the pressure injury knowledge of 75% of the home care nurses through an increase in Pieper-Zullowski Pressure Ulcer Knowledge Test [PZPUKT] scores. Aim four was to increase caregiver awareness of pressure injury prevention. Methods: This quality improvement project utilized pre/post testing of pressure injury rates and nursing knowledge. A three-phase policy revision, clinical education, and in-field implementation strategy centered around the NHS aSSKINg bundle was the intervention. Chi square analysis compared the pressure injury rates for statistical significance while two tailed t-testing was utilized to assess for changes in nursing education data. Results: 13 nurses and 77 patient caregiver dyads participated. A policy was created and presented meeting aim one. Pressure injury prevalence decreased by 12.82% (p= 0.3124), and incidence decreased by 35.89% (p=\u3c0.0001). There was no increase in pressure injuries throughout the study. Regarding nursing education, 87.5% of home care nurses attended the educational session and 100% improved their knowledge as demonstrated by increased PZPUKT scores (p=\u3c0.1). 100% of caregiver participants receiving the awareness intervention were able to teach back the concepts of the aSSKINg bundle. Conclusions: The aSSKINg bundle is a useful framework to create organization level pressure injury prevention programs. Education of staff and caregivers combined with a support surface supported by policy change can lead to decreases in pressure injuries, even in low resource environments

The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes.

The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells

Peroxiredoxin II Regulates Effector and Secondary Memory CD8+ T cell Responses

Reactive oxygen intermediates (ROI) generated in response to receptor stimulation play an important role in cellular responses. However, the effect of increased H2O2on an antigen-specific CD8+ T cell response was unknown. Following T cell receptor (TCR) stimulation, the expression and oxidation of peroxiredoxin II (PrdxII), a critical antioxidant enzyme, increased in CD8+ T cells. Deletion of PrdxII increased ROI, S phase entry, division, and death during in vitro division. During primary acute viral and bacterial infection, the number of effector CD8+ T cells in PrdxII-deficient mice was increased, while the number of memory cells were similar to those of the wild-type cells. Adoptive transfer of P14 TCR transgenic cells demonstrated that the increased expansion of effector cells was T cell autonomous. After rechallenge, effector CD8+ T cells in mutant animals were more skewed to memory phenotype than cells from wild-type mice, resulting in a larger secondary memory CD8+ T cell pool. During chronic viral infection, increased antigen-specific CD8+ T cells accumulated in the spleens of PrdxII mutant mice, causing mortality. These results demonstrate that PrdxII controls effector CD8+ T cell expansion, secondary memory generation, and immunopathology

Activation of muscle spindle afferents increases force fluctuations in the knee extensor muscles

The purpose of this project was to examine the effect of acute tendon vibration on fluctuations in force during contractions of the knee extensor muscles in young healthy subjects.College Honors

T-bet-mediated differentiation of the activated CD8+ T cell

The T-box transcription factor, T-bet promotes the differentiation of short-lived effector CD8+ T cells at the expense of central memory cells. How T-bet mediates these effects, and whether they are directly caused by T-bet alone are unknown, because expression of T-bet requires stimulation of the T cell by inflammatory and growth cytokines, which may have T-bet-independent functions involving T-cell differentiation. We developed an in vitro system of ectopic T-bet expression that avoids the effects of inflammatory cytokines to determine which aspects of the T-bet phenotype may be accounted for by T-bet alone. Ectopic T-bet expression by OT-I CD8+ T cells stimulated by the H2-Kb (SIINFEKL) complex and cultured with 2 ng/mL IL-2 induced a coordinated change in gene expression leading to down-regulation of CD127 and SOCS-1 and up-regulation of CD122 and IL-15 receptor α, switching the cellular survival cytokine from IL-7 to IL-15. T-bet expression and 2 ng/mL IL-2 also led to a capacity for IFN-γ and Fas ligand expression, confirming a role in eliciting these effector functions. Finally, ectopic T-bet promoted the expression of B lymphocyte-induced maturation protein 1 by OT-I cells in the presence of 20 ng/mL IL-2, providing a mechanism for the role of T-bet in driving terminal differentiation in concert with a high level of IL-2 receptor signalling

JAK2/IDH-mutant–driven myeloproliferative neoplasm is sensitive to combined targeted inhibition

Patients with myeloproliferative neoplasms (MPNs) frequently progress to bone marrow failure or acute myeloid leukemia (AML), and mutations in epigenetic regulators such as the metabolic enzyme isocitrate dehydrogenase (IDH) are associated with poor outcomes. Here, we showed that combined expression of Jak2V617Fand mutant IDH1R132Hor Idh2R140Q induces MPN progression, alters stem/progenitor cell function, and impairs differentiation in mice. Jak2V617FIdh2R140Q–mutant MPNs were sensitive to small-molecule inhibition of IDH. Combined inhibition of JAK2 and IDH2 normalized the stem and progenitor cell compartments in the murine model and reduced disease burden to a greater extent than was seen with JAK inhibition alone. In addition, combined JAK2 and IDH2 inhibitor treatment also reversed aberrant gene expression in MPN stem cells and reversed the metabolite perturbations induced by concurrent JAK2 and IDH2 mutations. Combined JAK2 and IDH2 inhibitor therapy also showed cooperative efficacy in cells from MPN patients with both JAK2mutand IDH2mutmutations. Taken together, these data suggest that combined JAK and IDH inhibition May offer a therapeutic advantage in this high-risk MPN subtype.Damon Runyon Cancer Research Foundation (DRG-2241-15)Howard Hughes Medical Institute (Faculty Scholars Award)Stand Up To CancerNational Cancer Institute (U.S.) (P50CA165962)National Cancer Institute (U.S.) (P30CA14051)Koch Institute for Integrative Cancer Research ( Dana-Farber Harvard Cancer Center Bridge Project)Leukemia & Lymphoma Society of America. Specialized Center of Research (SCOR) ProgramNational Institutes of Health (U.S.) (grant U54OD020355-01)National Institutes of Health (U.S.) (grant NCI R01CA172636)National Institutes of Health (U.S.) (grant R35CA197594)National Cancer Institute (U.S.) (Cancer Center Support Grant (P30 CA008747)

Effect of CMV and Aging on the Differential Expression of CD300a, CD161, T-bet, and Eomes on NK Cell Subsets

Natural killer cells are innate lymphoid cells involved in the defence against virus-infected cells and tumour cells. NK cell phenotype and function is affected with age and CMV latent infection. Aging affects the frequency and phenotype of NK cells and CMV infection also contributes to these alterations. Thus, a reduction of CD56bright NK cell subpopulation associated with age and an expansion of memory-like NK cells CD56dimCD57+NKG2C+ probably related to CMV-seropositivity have been described. NK cells express T-bet and Eomes transcription factors that are necessary for the development of NK cells. Here we analyse the effect of age and CMV-seropositivity on the expression of CD300a and CD161 inhibitory receptors and T-bet and Eomes transcription factors in NK cell subsets defined by the expression of CD56 and CD57. CD300a is expressed by the majority of NK cells. CD56bright NK cells express higher levels of CD300a than CD56dim NK cells. An increase in the expression of CD300a was associated with age whereas a decreased expression of CD161 in CD56dim NK cells was associated with CMV-seropositivity. In CD56dim NK cells an increased percentage of CD57+CD300a+ and a reduction in the percentage of CD161+CD300a+ cells were found to be associated with CMV-seropositivity. Regarding T-bet and Eomes transcription factors, CMV-seropositivity was associated with a decrease of T-bethi in CD56dimCD57+ NK cells from young individuals whereas Eomes expression was increased with CMV-seropositivity in both CD56bright and CD56dimCD57+/− (from middle-age and young individuals, respectively) and was decreased with ageing in all NK subsets from the three group of age. In conclusion, CMV infection and age induce significant changes in the expression of CD300a and CD161 in NK cell subsets defined by the expression of CD56 and CD57. T-bet and Eomes are differentially expressed on NK cell subsets and their expression is affected by CMV latent infection and ageing

Potential role of cholesterol in the migration of neurons containing gonadotropin-releasing hormone

Signaling by Sonic Hedgehog (Shh) is instrumental in the development of midline facial and forebrain structures. Signaling by Shh can be dependent upon conjugation with cholesterol. Structural abnormalities related to cholesterol depletion may be a result of a failure of Shh signaling. Disorders resulting in cholesterol depletion are often characterized in part by developmental malformations, including holoprosencephaly. Neurons that synthesize gonadotropin releasing hormone (GnRH; controls the reproductive axis) originate in the nasal compartment and migrate into the brain along a route that may depend upon proper Shh signaling. The current study was conducted to assess whether cholesterol-depleted enzyme Dhcr24-/- mice would affect the unique migration of GnRH neurons as they migrate to the brain.College Honors