PI3Kδ: a key driver of effector differentiation under conditions of T cell exhaustion

نویسندگان

چکیده

Abstract In chronic infection and cancer, prolonged antigen exposure drives a state of T cell hyporesponsiveness, called exhaustion. A small subset TCF1 +progenitor exhausted stem-like cells (pTex) cells, is required to maintain (Tex) respond checkpoint blockade. Understanding mechanisms regulating these populations may help identify approaches counter Phosphatidylinositol 3-kinase-d (PI3Kd) an important component signaling. We have found that TCF-1 repressed in CD8 +T from patients with Activated PI3K Delta Syndrome mouse model (Pik3cd E1020K/+mice) acute viral infections. How activated-PI3Kδ affects exhaustion unknown. Using LCMV clone 13 infection, we Pik3cd E1020K/+mice rapidly die, yet surviving mice recover faster than WT. RNA sequencing revealed decreased expression Tcf7, encoding TCF-1, antigen-specific along loss +Tim3 −CD8 +pTex upon cl13 infection. Tex were maintained during displayed effector-like phenotype, CX3CR1 +and KLRG1 +, increased effector functions, suggesting might induce early immunopathology increase clearance. P14 transfers, conjunction CRISPR-mediated gene disruption, FoxO1 leads +cells, whereas the at least partially cell-extrinsic. Our findings suggest PI3Kδ critical rheostat balances vs differentiation, providing insight for therapeutic strategies

برای دانلود باید عضویت طلایی داشته باشید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Notch controls effector CD8+ T cell differentiation

CD8+ T cell recognition of foreign antigen induces the expansion of the few T cells bearing an appropriate T cell receptor and the acquisition of effector functions. These effector CD8+ T (Te) cells eliminate the pathogen by secretion of cytokines or by direct cytotoxicity. Following this initial clonal expansion, 90-95% of the Te cells die while the few others further differentiate into memory...

متن کامل

Mapping Differentiation under Mixed Culture Conditions Reveals a Tunable Continuum of T Cell Fates

Cell differentiation is typically directed by external signals that drive opposing regulatory pathways. Studying differentiation under polarizing conditions, with only one input signal provided, is limited in its ability to resolve the logic of interactions between opposing pathways. Dissection of this logic can be facilitated by mapping the system's response to mixtures of input signals, which...

متن کامل

Cell differentiation in Dictyostelium under submerged conditions.

Hitherto it has not been possible to obtain spore and stalk cell differentiation of the cellular slime molds in submerged cultures. It is shown here that cells, when placed in roller tubes under an atmosphere of oxygen, will form clumps and differentiate in 48-72 hr into mature spores and stalk cells. Although differentiation occurs without the normal morphogenetic movements, there is the appea...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

ژورنال

عنوان ژورنال: Journal of Immunology

سال: 2023

ISSN: ['1550-6606', '0022-1767']

DOI: https://doi.org/10.4049/jimmunol.210.supp.226.05