The Impact of KLF2 Modulation on the Transcriptional Program and Function of CD8 T Cells

Abstract

Krüppel-like factor 2 (KLF2) is a transcription factor that is highly expressed in quiescent T lymphocytes and downregulated in effector T cells. We now show that antigen receptor engagement downregulates KLF2 expression in a graded response determined by the affinity of T cell antigen receptor (TCR) ligand and the integrated activation of protein kinase B and the MAP kinases ERK1/2. The present study explores the importance of KLF2 downregulation and reveals that the loss of KLF2 controls a select portion of the CD8 effector T cell transcriptional program. In particular, KLF2 loss is required for CD8 T cells to express the inflammatory chemokine receptor CXCR3 and for maximum clonal expansion of T cells. KLF2 thus negatively controls the ability of CD8 T cells to respond to the CXCR3 ligand CXCL10. Strikingly, the KLF2 threshold for restraining expression of CXCR3 is very low and quite distinct to the KLF2 threshold for restraining T cell proliferation. KLF2 is thus an analogue (tunable) not a digital (on/off) cellular switch where the magnitude of KLF2 expression differentially modifies the T cell responses.

Myocyte Enhancer Factor 2A Regulates Hydrogen Peroxide‐Induced Senescence of Vascular Smooth Muscle Cells Via microRNA‐143

“…KLF2, a downstream transcription factor of MEF2A (Kumar et al, ), could up‐regulate miR‐143 expression in endothelial cells (Hergenreider et al, ), and p‐AKT expression was opposite to KLF2 (Preston et al, ), suggesting that miR‐143 expression may be regulated by MEF2A. Consistently, our results have shown that up‐regulation of MEF2A promoted miR‐143 expression, which was inhibited by the KLF2 knockdown.…”

IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues

“…Moreover, overexpression of Klf2 lead to dramatic changes in expression of a broad range of genes related to trafficking, effector function, cytokine receptors, and transcriptional regulation [48]. Therefore, we next asked whether IL-15 complexes could alter effector functions of memory CD8 T cells.…”

pMHC affinity controls duration of CD8+ T cell–DC interactions and imprints timing of effector differentiation versus expansion

“…This pattern of localization correlated well with decreased CD69 and increased S1P1 expression patterns in Q4- and T4-primed cells as compared with N4-primed cells. Recent in vitro studies have shown that CXCR3 expression is rapidly induced on CD8 + T cells during primary stimulation in a pMHC affinity–dependent manner (Preston et al, 2013). We show that, also in vivo, N4-primed OT-I T cells showed the highest CXCR3 expression and moved to the outer cortical regions of LNs in a CXCR3-dependent manner, although in our hands, we were unable to detect CXCL9 or CXCL10 in LN sections (unpublished data).…”