Functional dynamics of Foxp3⁺ regulatory T cells in mice and humans

Abstract

Forkhead box protein 3 (Foxp3)(+) regulatory T (Treg) cells are critical mediators for the establishment of self-tolerance and immune homeostasis and for the control of pathology in various inflammatory responses. While Foxp3(+) Treg cells often control immune responses in secondary lymphoid tissues, they must also traffic to and persist within non-lymphoid tissues, where they integrate various environmental cues to coordinate and adapt their effector acitvities in these sites. In recent years, our group has made use of several mouse models, including the non-obese diabetic model of type 1 diabetes, to characterize the factors, which impact the homeostasis, function, and reprogramming potential of Foxp3(+) Treg cells in situ. In addition, our recent work shows that Foxp3(+) Treg cells possess distinct post-transcriptional mechanisms of gene regulation, namely mRNA translation, to modulate tissue-specific inflammatory responses. In humans, there is a pressing need for reliable markers of FOXP3(+) Treg cells and their related function in blood and tissue. Experimental progress in our group has enabled us to discover novel markers of FOXP3(+) Treg cell (dys)function and unique gene signatures that discriminate effector and Treg cells, as well as functional and dysfunctional FOXP3(+) Treg cells.

Categorical Analysis of Human T Cell Heterogeneity with One-Dimensional Soli-Expression by Nonlinear Stochastic Embedding

“…Tregs are widely known to possess remarkable plasticity and functional diversity (22,35,36), and recent focus on the balance of Tregs and pathogenic Th17 cells in autoimmune disease has drawn significant attention. One major difficulty in isolating this unique subset is the paucity and inconsistency of human Treg markers (35).…”

“…One major difficulty in isolating this unique subset is the paucity and inconsistency of human Treg markers (35). The master transcription factor FOXP3 (27) has been used as the most reliable marker of bona-fide Tregs.…”

Expression of Th17/Treg related molecules in gastric cancer tissues

“…Much of the pro-inflammatory functions of Th17 cells have been attributed to the secretion of IL-17 (15,16). Tregs, as an immunosuppressive subset of T lymphocytes, were found to express the signature FoxP3 transcription factor, which is critical for their development and regulatory functions (17). Treg-mediated immune suppression and tolerance to self-components Th17 and Treg have been studied in many malignancies including gastric cancer.…”

“…FoxP3 is considered the key transcription factor of Treg, and TGF-β1 is one of the main effectors of Tregs (17). The expression of FoxP3 and TGF-β1 in gastric cancer tissues reflected the distribution and function of Treg in tumor microenvironment.…”

Post-Transcriptional and Translational Mechanisms of Regulation of Gene Expression in T Cell Subsets

“…T REG cells can differentiate in the thymus or under unique stimulatory conditions in the periphery. As such, The T REG cell pool consists of thymic-derived T REG cells (tT REG ) as well as peripherally induced T REG cells (pT REG ) cells [43]. Foxp3 expression in tT REG cells has been shown to be dependent on the binding of several transcription factors to both the foxp3 promoter and conserved noncoding sequences (CNS), which function as enhancers of foxp3 transcription [44].…”