Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3

Abstract

FoxP3+ T regulatory (Treg) cells have a fundamental role in immunological tolerance, with transcriptional and functional phenotypes that demarcate them from conventional CD4+ T cells (Tconv). Differences between these two lineages in the signaling downstream of T-cell receptor-triggered activation have been reported, and there are different requirements for some signaling factors. Seeking a comprehensive view, we found that Treg cells have a broadly dampened activation of several pathways and signaling nodes upon TCR-mediated activation, with low phosphorylation of CD3ζ, SLP76, Erk1/2, AKT, or S6 and lower calcium flux. In contrast, STAT phosphorylation triggered by interferons, IL2 or IL6, showed variations between Treg and Tconv in magnitude or choice of preferential STAT activation but no general Treg signaling defect. Much, but not all, of the Treg/Tconv difference in TCR-triggered responses could be attributed to lower responsiveness of antigen-experienced cells with CD44hi or CD62Llo phenotypes, which form a greater proportion of the Treg pool. Candidate regulators were tested, but the Treg/Tconv differential could not be explained by overexpression in Treg cells of the signaling modulator CD5, the coinhibitors PD-1 and CTLA4, or the regulatory phosphatase DUSP4. However, transcriptome profiling in Dusp4-deficient mice showed that DUSP4 enhances the expression of a segment of the canonical Treg transcriptional signature, which partially overlaps with the TCR-dependent Treg gene set. Thus, Treg cells, likely because of their intrinsically higher reactivity to self, tune down TCR signals but seem comparatively more attuned to cytokines or other intercellular signals.

TCR Signal Strength Regulates Akt Substrate Specificity To Induce Alternate Murine Th and T Regulatory Cell Differentiation Programs

“…In nTregs, the CD3θ isoform dominated suggesting that the alternative splicing observed during Treg induction remains after differentiation. This may provide an explanation for the reduced TCR signaling in Treg cells, which was recently investigated (44). This study examined the role of several Treg-specific negative regulators, such as CTLA-4, PD-1, CD5 and DUSP4, but these were not found to be responsible for the reduced signaling in Treg (44).…”

“…This may provide an explanation for the reduced TCR signaling in Treg cells, which was recently investigated (44). This study examined the role of several Treg-specific negative regulators, such as CTLA-4, PD-1, CD5 and DUSP4, but these were not found to be responsible for the reduced signaling in Treg (44). Together, these results suggest that splicing regulated by Akt functions to rewire the canonical TCR signaling pathway to drive alternate CD4 + T cell differentiation programs.…”

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

“…Treg cells are thought to develop within a narrow window of TCR–MHC binding affinity above the threshold of negative selection, thus possessing a TCR repertoire skewed towards self‐recognition . The signal immediately downstream of the TCR is constricted in Treg cells compared with conventional T cells, protecting, perhaps, against stimulation‐induced apoptosis – but rendering them especially vulnerable to inhibition of the TCR signal (Tanaka et al ., under review).…”

CD25 signaling regulates the function and stability of peripheral Foxp3+ regulatory T cells derived from the spleen and lymph nodes of mice

“…NS, not significant. * p < 0.05, ** p < 0.01. other groups (Yan et al, 2015;Diaz et al, 2015). In the lymph nodederived Tregs, Foxp3 expression was significantly reduced from 95.2% ± 2.3% on day 0 to 36.8% ± 7.8% and 23.4% ± 4.2% on days 4 and 6, respectively.…”