Transcription factor ELF4 controls the proliferation and homing of CD8+ T cells via the Krüppel-like factors KLF4 and KLF2

Abstract

Transcription factors that regulate quiescence, proliferation, and homing of lymphocytes are critical for effective immune system function. In the present study, we demonstrated that the transcription factor ELF4 directly activates the tumor suppressor KLF4 downstream of T cell receptor (TCR) signaling to induce cell-cycle arrest in naïve CD8+ T cells. Elf4- and Klf4-deficient mice accumulated CD8+CD44hi T cells during steady-state conditions and generated more memory T cells after immunization. The homeostatic expansion of CD8+CD44hi T cells in Elf4-null mice resulted in a redistribution of cells to non-lymphoid tissue due to reduced expression of the transcription factor KLF2, and the surface proteins CCR7 and CD62L. This work describes the combinatorial role of lymphocyte-intrinsic factors on T cell homeostasis, activation and homing.

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

“…For example, c-Myc is required for the proliferation of thymocytes at the preTCR checkpoint [9], and Klf4 is a key regulator of monocyte development [10], B-cell numbers and activation-induced B-cell proliferation [11], and quiescence of CD8 + T cells [12], and is required for the production of IL-17 [13]. Gene expression profiling studies have also shown that Klf4 is expressed in mouse and human thymocytes [14][15].…”

ELF4 (E74-like factor 4 (ets domain transcription factor))

“…ELF4 plays an important role in the development and function of NK and NK T-cells and in innate immunity (Lacorazza et al, 2002). It controls the proliferation and homing of CD8+ Tcells via the Kruppel-like factors KLF4 and KLF2 (Yamada et al, 2009;Yamada et al, 2010). ELF4 regulates hematopoietic stem cell quiescence and self-renewal (Lacorazza et al, 2006;Liu et al, 2009).…”

Finding a fairy in the forest: ELF4, a novel and critical element of type I interferon responses

“…Previous studies have revealed that the ETS family transcription factor ELF4 takes part in various cellular processes, such as tumorigenesis, 4 the DNA damage response 5 and cell cycle regulation. 6 Despite the growing body of research in this field, the exact physiological role of ELF4 remained unknown.In their article, You et al demonstrate that ELF4 is a critical factor in the regulation of type I IFN responses and plays a significant role in the antiviral host defense. ELF4 was shown to interact with STING, as demonstrated by coimmunoprecipitation analysis in HeLa cells.…”

“…Previous studies have revealed that the ETS family transcription factor ELF4 takes part in various cellular processes, such as tumorigenesis, 4 the DNA damage response 5 and cell cycle regulation. 6 Despite the growing body of research in this field, the exact physiological role of ELF4 remained unknown.…”

“…These findings are consistent with previous reports that showed the importance of ELF4 in antiviral cellular immune responses. 6,7 Interestingly, the group also found that ELF4 controls viral replication in vivo by directly regulating the type I IFN response, not through the contribution of natural killer and natural killer T cells or cytotoxic T lymphocytes.…”