Abstract
T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4+ Treg cells are well characterized whereas the role of CD8+ Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8+FOXP3+ Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4+ Treg cells. But how FOXP3 is induced and maintained in tumor-CD8+ Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8+ lineage-specific transcription factor, binds at the FOXP3-promoter to induce its transcription. In addition to promoter activation, involvement of cis-elements CNS1 and CNS2 in the transcriptional regulation of FOXP3 was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the FOXP3 transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for FOXP3 in naïve CD8+ T cells. Whereas in CD8+ Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of FOXP3. Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.
Highlights
T-regulatory cells (Tregs) play a pivotal role in the development and maintenance of peripheral immune tolerance as defects in their compartment lead to severe autoimmune diseases
We disclosed the mechanisms of development and function of CD8+ Treg cells in breast tumor microenvironment, emphasizing the transcriptional regulation of their FOXP3 gene
Most of the previous studies have described the regulation of FOXP3 in CD4+ Treg cells; CD4+ and CD8+ cells have different lineage-specific transcription machinery which suggests that the regulation of FOXP3 in CD4+ and CD8+ Treg cells can differ
Summary
T-regulatory cells (Tregs) play a pivotal role in the development and maintenance of peripheral immune tolerance as defects in their compartment lead to severe autoimmune diseases. In CD4+ Treg cells, FOXP3 induction is coupled with the activation of TCR/NFAT-NFκB-signalling or by TGFβ/SMAD3-signaling[2, 10] In addition to these factors other, transcription factors, viz; GATA3, RUNX3, and RUNX1 play pivotal roles in the regulation of Foxp[3] gene expression[11, 12]. Since CTLA4 is transcriptionally activated by FOXP3, we used this co-stimulatory molecule as a surface signature for the isolation of tumor-CD8+ Treg cells for our study Exploiting these cells we could successfully show that transcriptional activation of FOXP3-promoter is associated with chromatin modification and binding of SMAD3, GATA3, and RUNX3 at the different non-coding conserved sequence (CNS) and the promoter regions of FOXP3. This study may open a new way to target CD8+ Treg cells and potentiates the antitumor immunity during cancer immunotherapy
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