Control of CD8 T cell proliferation and terminal differentiation by active STAT5 and CDKN2A/CDKN2B

Abstract

SummaryCD8 T cells used in adoptive immunotherapy may be manipulated to optimize their effector functions, tissue-migratory properties and longterm replicative potential. We reported that antigen-stimulated CD8 T cells transduced to express an active form of the transcription factor signal transducer and activator of transcription 5 (STAT5CA) maintained these properties upon adoptive transfer. We now report on the requirements of STAT5CA-expressing CD8 T cells for cell survival and proliferation in vivo. We show that STAT5CA expression allows for greater expansion of T cells in vivo, while preserving dependency on T-cell-receptor-mediated tonic stimulation for their in vivo maintenance and return to a quiescent stage. STAT5CA expression promotes the formation of a large pool of effector memory T cells that respond upon re-exposure to antigen and present an increased sensitivity to cc receptor cytokine engagement for STAT5 phosphorylation. In addition, STAT5CA expression prolongs the survival of what would otherwise be short-lived terminally differentiated KLRG1-positive effector cells with up-regulated expression of the senescence-associated p16 INK4A transcripts. However, development of a KLRG1-positive CD8 T cell population was independent of either p16 INK4A or p19 ARF expression (as shown using T cells from CDKN2A À/À mice) but was associated with expression of transcripts encoding p15 INK4B , another protein involved in senescence induction. We conclude that T-cell-receptor-and cytokine-dependent regulation of effector T cell homeostasis, as well as mechanisms leading to senescent features of a population of CD8 T cells are maintained in STAT5CA-expressing CD8 T cells, even for cells that are genetically deficient in expression of the tumour suppressors p16 INK4A and p19 ARF .

Long noncoding RNA SYISL regulates myogenesis by interacting with polycomb repressive complex 2

“…Recent studies have reported that some lncRNAs, including Xist, APTR, and ANCR, can recruit EZH2 to epigenetically silence the cdkn1a (cyclin-dependent kinase inhibitor 1A, p21) gene, thereby promoting cell proliferation (39)(40)(41). p21 is an important cell-cycle regulator that restrains the cell cycle by inhibiting CDKs in mouse embryonic fibroblasts (42,43). In this study, the inhibitory effects of p21 on cell proliferation were confirmed by EdU staining in C2C12 cells (SI Appendix, Fig.…”

Structure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents

“…STATs play also a major role in regulating CD8 T cell responses ( 29 ). In fact, expression of a constitutively active form of STAT5 in murine CD8 T cells promotes the expression of genes controlling effector molecules, proliferation, and tissue homing, as well as transcription factors required for CD8 T cell function, such as T-bet and Eomes ( 30 – 32 ). STAT proteins have also been shown to play important roles in NK function (for a review, see reference 33 ).…”

Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders

“…111,112 The forced expression of the active form of STAT5 prolongs the survival of what would otherwise be short-lived terminally differentiated effector T cells. 113 PI3K/Akt signaling has been shown to be activated more robustly in longlived memory precursor T cells than in short-lived effector cells, and the functional suppression of PI3K/Akt can lead to defective CD8 + memory T cell formation in vivo. 111,114 However, constitutive PI3K/Akt activation does not enhance memory CD8 + T cell survival but rather represses IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and Bcl-2 expression (Fig.…”