FOXP1 is a regulator of quiescence in healthy human CD4⁺ T cells and is constitutively repressed in T cells from patients with lymphoproliferative disorders

Abstract

The forkhead box P1 (FOXP1) transcription factor has been shown to regulate the generation and maintenance of quiescent naïve murine T cells. In humans, FOXP1 expression has been correlated with overall survival in patients with peripheral T-cell lymphoma (PTCL), although its regulatory role in T-cell function is currently unknown. We found that FOXP1 is normally expressed in all human leukocyte subpopulations. Eur. J. Immunol. 2017. 47: 168-179 Immunomodulation and immune therapies 169 IntroductionCellular quiescence defines cell cycle arrest in the G0 phase, which is characterized by lower rates of transcription, translation, and metabolism thereby reducing the consumption of nutrients required to maintain cellular activities. This reversible state may indirectly deter malignant transformation by protecting cells from metabolic damage. In lymphocytes, quiescence is distinct from anergy and senescence and can be reversed by antigenic stimulation. Initially, quiescence was thought to result from the absence of activating signals, but growing evidence from murine models and in vitro cell line studies reveals that quiescence is actively controlled by a transcriptional program [1]. Several transcription factors (TF) have been shown to play a role in T-cell quiescence, including LKLF, a zinc finger TF and TOB1, an anti-proliferative TF [2,3]. Expression levels of these transcriptional regulators are high in naïve T cells and decrease dramatically following TCR crosslinking. Their suppression decreases the T-cell activation threshold, resulting in increased T-cell proliferation and effector functions. Murine studies have shown that a forkhead box (FOX) TF, FOXP1, is essential for the generation of quiescent naïve T cells during thymocyte development and maintaining quiescence in the periphery [4,5].The FOX TF family performs diverse functions, including regulating development and organogenesis, metabolism, and immune responses. FOX TF are identified by a conserved 110-amino acid DNA-binding (winged helix) domain [6,7]. Members of the FOXP subfamily, including FOXP1-FOXP4, contain a zinc finger domain and a leucine zipper motif and form homo-or heterodimers [8]. In the murine immune system, FOXP1 acts as an essential transcriptional regulator of B-cell lymphopoiesis by directly regulating the B-cell specific Erag enhancer [9]. Moreover, its downregulation is required for B-cell transit through the germinal center (GC) [10]. FOXP1 is also expressed in monocytes and has been shown to regulate their differentiation both in human cell lines and in a murine model where it was also shown to control macrophage functions [11,12]. A recent study demonstrated that upregulation of FOXP1 in CD8 + T cells drives T-cell unresponsiveness in cancer by blocking proliferation and major T cell functions, including degranulation of cytotoxic granules and cytokine release. This state, which is distinct from anergy and exhaustion, involves FOXP1 and Smad2/Smad3 interactions, both translocated to the nucleus in response to TGF-β signalin...

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

“…This TF is associated with a quiescent central memory T cell (Tcm) phenotype, consistent with the hypothesis that cells that adopt a quiescent Tcm phenotype are more prone to latent infection (Garaud et al, 2017). Interestingly, a related Forkhead TF, FOXO1, has also recently been reported to promote HIV latency (Roux et al, 2019;Vallejo-Gracia et al, 2020).…”

Immune Checkpoint Molecules on Tumor-Infiltrating Lymphocytes and Their Association with Tertiary Lymphoid Structures in Human Breast Cancer

“…Immunofluorescence (IF) staining was performed manually on FFPE tumor tissues [4 µm sections; detailed in Ref. ( 42 )]. After washing, slides were mounted with ProLong Gold anti-fade mounting medium with DAPI (Thermo Scientific) and visualized on a Zeiss LSM 710 confocal microscope equipped with a ×20/0.8 Plan-Apochromat dry objective (Carl Zeiss, Oberkochen, Germany).…”

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis

“…The top gene according to a CpG of the EPIMMUNE signature located in a regulatory region with the highest ANOVA value and greatest CpG methylation difference between PD-1 blockade responders and non-responders in the discovery cohort (Table S1), with additional biological plausibility, was the T-cell-related forkhead box P1 (FOXP1) transcription factor. 32,33 The unmethylated status of FOXP1 has been associated with quiescent naïve CD4+ Tcells, 32,33 so it is reasonable to speculate that the release of the PD-1/PD-L1 immunosuppression axis through the use of the anti-PD-1 antibody will allow the activation of these naïve T-cells, an event that has already been linked to FOXP1 hypermethylation. 32,33 FOXP1 unmethylated status was associated with extended PFS in the studied discovery cohort (HR=0.423, P=0.032; 95% CI=0.192-0.928; log-rank P=0.027) ( Fig.…”