Differential roles of KLF4 in the development and differentiation of CD8+ T cells

Abstract

The transcription factor Krüppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naïve CD8+ T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8+ T cells upon infection. Loss of KLF4 had minimal effect on thymic T cell development and distribution of mature T cells in the spleen, blood, and lymph nodes. KLF4-deficient naïve CD8+ T cells also displayed normal homeostatic proliferation upon adoptive transfer into lymphopenic hosts. However, activation of KLF4-deficient naïve CD8+ T cells by in vitro TCR crosslink and co-stimulation resulted in increased proliferation. Furthermore, naïve KLF4-deficient OT-I CD8+ T cells generated increased numbers of functional memory CD8+ T cells compared to wild type OT-I CD8+ T cells co-injected in the same recipient in both primary and recall responses to Listeria monocytogenes-OVA. Collectively, our data demonstrate that KLF4 regulates differentiation of functional memory CD8+ T cells while sparing development and homeostasis of naïve CD8+ T cells.

K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

“…ELF4 and KLF4 play essential roles in TCR-mediated proliferation because these transcription factors regulate the cell cycle910. To determine whether Mule has effects on ELF4 and/or KLF4, we subjected purified WT and TMKO CD4 + and CD8 + T cells at steady-state to immunoblotting and detected substantial elevations of ELF4 and KLF4 proteins in TMKO T cells compared with the WT (Fig.…”

“…We next turned to KLF4, since we now knew that this transcription factor, which controls T-cell proliferation through cell cycle regulators910, was a Mule substrate. We speculated that the defective proliferation of TCR-stimulated TMKO T cells might be caused by KLF4 that had accumulated due to the lack of Mule-mediated ubiquitination (followed by degradation) in these cells.…”

“…The transcription factors KLF4 and ELF4 negatively regulate CD8 + T-cell proliferation and differentiation through their control of cyclin-dependent kinases (CDK) and their inhibitors (CDKI)910. KLF4 protein diminishes in response to TCR engagement, leading to downregulation of CDKI such as p21 and p27 and the entrance of CD8 + T cells into the cell cycle.…”

“…KLF4 protein diminishes in response to TCR engagement, leading to downregulation of CDKI such as p21 and p27 and the entrance of CD8 + T cells into the cell cycle. CD8 + T cells lacking either klf4 or elf4 hyperproliferate upon TCR engagement910. In CD4 + T cells, KLF4 binds to the IL17a promoter and drives Th17 differentiation independently of RORγt1112.…”

Role of the reprogramming factor KLF4 in blood formation

“…KLF4 was initially termed gut KLF because of its discovery in the intestinal epithelium, although KLF4 is also expressed in epithelial cells from other tissues, such as the skin and lung [4,5]. In addition to postmitotic and terminally differentiated epithelial cells, KLF4 is expressed in other tissues, such as the thymus, testis, cornea, neonatal myocytes, and NK and T cells [6][7][8][9][10]. In cancer, KLF4 has dual functions as a tumor suppressor (i.e., colon and stomach cancer) and as an oncogene (i.e., breast cancer), which has been reviewed extensively elsewhere [3,[11][12][13].…”