Abstract
In T cells, T cell receptor (TCR) signaling initiates downstream transcriptional mechanisms for T cell activation and differentiation. Foxp3-expressing regulatory T cells (Treg) require TCR signals for their suppressive function and maintenance in the periphery. It is, however, unclear how TCR signaling controls the transcriptional program of Treg. Since most of studies identified the transcriptional features of Treg in comparison to naïve T cells, the relationship between Treg and non-naïve T cells including memory-phenotype T cells (Tmem) and effector T cells (Teff) is not well understood. Here, we dissect the transcriptomes of various T cell subsets from independent datasets using the multidimensional analysis method canonical correspondence analysis (CCA). We show that at the cell population level, resting Treg share gene modules for activation with Tmem and Teff. Importantly, Tmem activate the distinct transcriptional modules for T cell activation, which are uniquely repressed in Treg. The activation signature of Treg is dependent on TCR signals and is more actively operating in activated Treg. Furthermore, by using a new CCA-based method, single-cell combinatorial CCA, we analyzed unannotated single-cell RNA-seq data from tumor-infiltrating T cells, and revealed that FOXP3 expression occurs predominantly in activated T cells. Moreover, we identified FOXP3-driven and T follicular helper-like differentiation pathways in tumor microenvironments, and their bifurcation point, which is enriched with recently activated T cells. Collectively, our study reveals the activation mechanisms downstream of TCR signals for the bifurcation of Treg and Teff differentiation and their maturation processes.
Highlights
T cell receptor (TCR) signaling activates NFAT, AP-1, and NF-κB [1], which induces the transcription of interleukin (IL)-2 and IL-2 receptor (R) α-chain (Il2ra, CD25)
We have extended the application of correspondence analysis (CCA) to single-cell analysis of unannotated cells [single-cell combinatorial CCA (SC4A)] and revealed the dynamic regulation of T cell activation-induced differentiation processes in tumor-infiltrating T cells at the single-cell level
Tcra KO CD44lo naïve Treg showed the lowest scores, and these scores were lower than WT CD44lo naïve Treg (Figure 6B). These results indicate that TCR signaling is required for the constitutive activation status of Treg, especially CD44hi activated Treg (aTreg), and suggest that these aTreg are more enriched with the cells that received TCR signals recently, compared to CD44lo naïve Treg
Summary
T cell receptor (TCR) signaling activates NFAT, AP-1, and NF-κB [1], which induces the transcription of interleukin (IL)-2 and IL-2 receptor (R) α-chain (Il2ra, CD25). IL-2 signaling has key roles in immunological tolerance [2] This is partly mediated through CD25-expressing regulatory T cells (Treg), which constitutively express FoxP3, the lineage-specific transcription factor of Treg [3], and suppress. TCR signaling induces the transient expression of FoxP3 in any T cells in humans [5] and in mice in the presence of IL-2 and TGF-β [6]. These suggest that FoxP3 can be actively induced as a negative feedback mechanism for the T cell activation process, especially in inflammatory conditions in tissues [7]. The T cell activation processes may dynamically control Treg phenotype and function during immune response and homeostasis
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