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

Takeshi Yamada et al., Nat. Immunol. 10:618-26, 2009

Speaker: Tsung-Hao Chang (張琮浩)                        Time: 14:10-15:00, Dec. 23, 2009

Commentator: Dr. Huan-Yao Lei (黎煥耀 老師)        Place: Room 601

Abstract

  Naïve and memory T cells undergo homeostatic proliferation in peripheral lymphoid organs for maintaining T cell pool when reduced numbers of nascent T cells are generated from thymus in later life¹.  T cell homeostatic signals require self-pMHC complexes and cytokines.  However, the downsteam signaling and regulators are still poorly understood.  ELF4 has been reported to control the balance between activation and quiescence of hematopoietic stem cells².  In this paper, the authors hypothesized that naïve T cell homeostasis may be also controlled by ELF4.  Their results demonstrated that the Elf4^-/- naïve and memory-like CD8⁺ T cells proliferated more than did wild-type CD8⁺ T cells under homeostatic condition and antigen stimulation.  The increased proliferation in Elf4^-/- CD8⁺ T cells was due to lower threshold of cell cycle entry.  The enhanced T cell proliferation in Elf4^-/- mice caused splenomegaly and expansion of memory-like T cells in spleen, lung, liver, blood and bone marrow, but not lymph nodes.  These expanded T cells showed reduced expression of surface CD62L molecules that help lymphocytes home to lymph nodes.  The reduction of CD62L expression in Elf4^-/- CD8⁺ T cells was caused by the down-regulation of KLF2, a transcription factor that has been shown to drive CD62L gene expression³.  By microarray screening, a Klf2 homology gene, Klf4, was identified to be down-regulated in naïve Elf4^-/- T cells. The authors confirmed that ELF4 bound to the promoter of Klf4 gene and regulated KLF4 expression.  KLF4 is a transcription factor that regulates cell proliferation and differentiation.  Klf4^-/- mice showed similar phenotypes and expansion of T cell pool with Elf4^-/- mice.  In conclusion, ELF4 plays an important role in regulating T cell pool and homing and maintaining naïve T cell quiescence via transcription factors KLF2 and KLF4.

References:

1.          Surh, C.D. and Sprent, J. Homeostasis of naïve and memory T cells. Immunity 29: 848–862, 2008.

2.         Lacorazza, H.D. et al. The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. Cancer Cell 9: 175–187, 2006.

3.          Bai, A. et al. Krüppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J. Immunol. 178: 7632–7639, 2007.