Abstract
CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Treg cells to the site of inflammation. However, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated infection models. Our analysis defined a set of Th1-specific co-inhibitory receptors and cytotoxic molecules that are specifically expressed in Treg cells during Th1 immune responses in mice and humans. Among these, we identified the novel co-inhibitory receptor CD85k as a functional predictor for Treg-mediated suppression specifically of Th1 responses, which could be explored therapeutically for selective immune suppression in autoimmunity.
Highlights
CD4+Foxp3+ regulatory T cells (Treg) play a pivotal role in maintaining immune self-tolerance and homeostasis by modulating the action of T effector cell subsets
We found Treg specialization into T-bet+CXCR3+ Treg cells to be a mutual feature of all three infections but the peak of activation was observed at different time points depending on the infectious setting (Figures 1A–D)
The peak in CXCR3 expression coincided with peak expression of Treg effector molecules such as the ectonucleotidase CD39, the receptor CD103, which is expressed on activated and highly suppressive Treg cells [30], and the co-inhibitory receptors CTLA-4 and PD-1, which have been shown to promote the suppressive function of Treg cells [31, 32] (Figure 1E)
Summary
CD4+Foxp3+ regulatory T cells (Treg) play a pivotal role in maintaining immune self-tolerance and homeostasis by modulating the action of T effector cell subsets. The suppressive mechanisms of Treg cells are highly diverse and target various effector populations, depending on the context of their activation, the anatomical location, and specific environmental signals. These functions include (i) the secretion of suppressive cytokines (IL-10, TGF-β, IL-35) [5, 6], (ii) competition for stimulatory signals with effector T cells and antigen-presenting cells (APCs) through high and sustained expression of co-inhibitory receptors (CTLA-4, PD-1) [7, 8] (iii) metabolic disruption (IL-2 deprivation, generation of pericellular adenosine through CD73 and CD39) [9] as well as (iv) granzyme-mediated cytolysis [10]. In response to specific cues from the immune environment, Treg cells acquire co-expression of Foxp with T helper cell lineage-specific
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