Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8⁺ T lymphocytes

Abstract

KLF10 has recently elicited significant attention as a transcriptional regulator of transforming growth factor-β1 (TGF-β1) signaling in CD4+ T cells. In the current study, we demonstrate a novel role for KLF10 in the regulation of TGF-β receptor II (TGF-βRII) expression with functional relevance in antiviral immune response. Specifically, we show that KLF10-deficient mice have an increased number of effector/memory CD8+ T cells, display higher levels of the T helper type 1 cell-associated transcription factor T-bet, and produce more IFN-γ following in vitro stimulation. In addition, KLF10−/− CD8+ T cells show enhanced proliferation in vitro and homeostatic proliferation in vivo. Freshly isolated CD8+ T cells from the spleen of adult mice express lower levels of surface TGF-βRII (TβRII). Congruently, in vitro activation of KLF10-deficient CD8+ T cells upregulate TGF-βRII to a lesser extent compared with wild-type (WT) CD8+ T cells, which results in attenuated Smad2 phosphorylation following TGF-β1 stimulation compared with WT CD8+ T cells. Moreover, we demonstrate that KLF10 directly binds to the TGF-βRII promoter in T cells, leading to enhanced gene expression. In vivo viral infection with Daniel's strain Theiler's murine encephalomyelitis virus (TMEV) also led to lower expression of TGF-βRII among viral-specific KLF10−/− CD8+ T cells and a higher percentage of IFN-γ-producing CD8+ T cells in the spleen. Collectively, our data reveal a critical role for KLF10 in the transcriptional activation of TGF-βRII in CD8+ T cells. Thus, KLF10 regulation of TGF-βRII in this cell subset may likely play a critical role in viral and tumor immune responses for which the integrity of the TGF-β1/TGF-βRII signaling pathway is crucial.

Fine-tuning innate and adaptive immune responses: another KLFhanger. Focus on “Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes”

“…For example, it would be of interest to assess the relative ratio of CD8 ϩ Tregs versus CD8 ϩ T cell effectors in response to viral pathogens. The expansion of KLF10 Ϫ/Ϫ CD8 ϩ T cells observed by Papadakis et al (6) aligns well with the known role of TGF-␤ on CD8 ϩ T cell homeostasis-abrogation of TGF-␤ signaling leads to marked T cell expansion including memory CD8 ϩ T cells (4). However, whether KLF10 is the primary downstream mediator of this TGF-␤1-driven CD8 T cell expansion remains to be determined.…”

“…Previous studies indicate that TGF-␤ signaling induces CD8 ϩ T cell differentiation by increasing IL-7R␣ expression as well as emigration of CD8 ϩ T cell effectors from the spleen to the organs such as the gut by regulating integrin ␣ 4 ␤ 7 expression. While Papadakis et al (6). found no differences in the total number of peripheral CD8 ϩ T cells in KLF10 Ϫ/Ϫ mice compared with wild-type (WT) mice, the ratio of CD8 ϩ T cell effectors to naïve T cells was markedly increased in KLF10 Ϫ/Ϫ mice.…”

“…In this issue of AJP-Cell, Papadakis et al (6) identify a new transcriptional regulator of CD8 ϩ T cell effector function termed Krüppel-like factor 10 (KLF10) by its ability to modulate the TGF-␤ receptor type II (TGF-␤RII) expression and downstream TGF-␤ signaling (Fig. 1).…”

“…Consistent with the findings in CD4 ϩ KLF10 Ϫ/Ϫ T cells, Papadakis et al also identify that TGF-␤ signaling is impaired in CD8 ϩ KLF10 Ϫ/Ϫ T cells; however, in contrast to the reduced expression of TGF-␤1 in both KLF10 Ϫ/Ϫ CD4 ϩ CD25 Ϫ T cells and CD4 ϩ CD25 ϩ T regs (2), KLF10 Ϫ/Ϫ CD8 ϩ T cells exhibit reduced expression for TGF-␤RII. In CD4 ϩ T cells, KLF10 binds the proximal TGF-␤1 promoter (2), whereas in CD8 ϩ T cells, KLF10 targets the proximal TGF-␤RII promoter (6). While studies for whether KLF10 regulates TGF-␤1 expression in CD8 ϩ T cells were not explored, expression of TGF-␤RII was similar in WT and KLF10 Ϫ/Ϫ CD4 ϩ CD25 Ϫ T cells and CD4 ϩ CD25 ϩ T regs (2).…”

Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

“…In fact, these considerations led us in this study to search for cellular and molecular mechanisms that acting downstream of TGF-␤ signaling may contribute to colitis. In this regard, recent studies have identified a role for TGF-␤-inducible early gene 1 or KLF10, which belongs to the family of Sp1/Krüppel-like zinc finger transcription factors (31), in T lymphocytes and innate immune cells (5,23,34,39).…”