The Transcription Factor ZFfx Regulates Peripheral T Cell Self-renewal and Proliferation

Peripheral T lymphocytes share many functional properties with hematopoietic stem cells (HSCs), including long-term maintenance, quiescence, and latent proliferative potential. In addition, peripheral T cells retain the capacity for further differentiation into a variety of subsets, much like HSCs. While the similarities between T cells and HSC has long been hypothesized, the potential common genetic regulation of HSCs and T cells has not been widely explored. We have studied the T cell-intrinsic role of Zfx, a transcription factor specifically required for HSC maintenance. We report that T cell-specific deletion of Zfx caused age-dependent depletion of naïve peripheral T cells. Zfx-deficient T cells failed to undergo homeostatic proliferation in a lymphopenic environment, and showed impaired antigen-specific expansion and memory response. In addition, the invariant natural killer T cell (iNKT) cell compartment was severely reduced. Transcriptome analysis identified target genes of Zfx in T cells which are shared with HSCs. Zfx-deficient T cells also revealed activation of the stress response, elevated expression of cell cycle inhibitor Cdkn1a/p21 and reduced telomerase activity. These studies identify Zfx as an important regulator of peripheral T cell maintenance and expansion, and highlight the common molecular basis of HSC and T cell homeostasis. Naïve CD4+CD62L+ splenocytes were sorted from spleens of control or Zfx T cell conditional knockout mice, aged 6-8 weeks. Cell stimulation involved adding the CD4+CD62L+ T cells to plate-bound aCD3 (3mg/mL) and aCD28 (2mg/mL); these cells were collected after 12 hours.