Stability and Maintenance of Foxp3+ Treg Cells in Non-lymphoid Microenvironments

Abstract

Foxp3⁺ Treg cells are indispensable for maintaining self-tolerance in secondary lymphoid organs (SLOs). However, Treg cells are also recruited to non-lymphoid tissues (NLTs) during inflammation. Recent advances in the understanding of Treg cell biology provided us with molecular mechanisms-both transcriptional and epigenetic-that enable Treg cells to retain their identity in an inflammatory milieu that is per se hostile to sustained expression of high levels of Foxp3. While Treg cells are recruited to sites of inflammation in order to resolve inflammation and re-establish appropriate organ function, it is increasingly recognized that a series of inflammatory (but also non-inflammatory) perturbations of organ function lead to the constitution of relatively long lived populations of Treg cells in NLTs. NLT Treg cells are heterogeneous according to their respective site of residence and it will be an important goal of future investigations to determine how these NLT Treg cells are maintained, e.g., what the role of antigen recognition by NLT Treg cells is and which growth factors are responsible for their self-renewal in the relative deficiency of IL-2. Finally, it is an open question what functions NLT Treg cells have besides their role in maintaining immunologic tolerance. In this review, we will highlight and summarize major ideas on the biology of NLT Treg cells (in the central nervous system but also at other peripheral sites) during inflammation and in steady state.

Keywords: Foxp3; Treg—regulatory T cell; central nervous system; heterogeneity; non-lymphoid tissues; stability.

Figure 1

Population dynamics and maintenance of Treg cells in NLTs. During an adaptive immune response in NLT (e.g., in the central nervous system during EAE) conventional T cells (Teff) infiltrate the target tissue and expand providing sufficient IL-2 to also drive the differentiation and expansion of Treg cells. After contraction of the conventional effector T cell (Teff) population (due to active regulation by Treg cells), IL-2 becomes limiting and persisting Treg cells likely depend on alternative signals for self-renewal. Here, signals that activate the NF-κB pathway might be important cues not only for NLT function but also for their maintenance (31). TCR triggering of Treg cells and downstream modulation of the TCR signal by the transcriptional modulator IRF4 is a non-redundant event in the differentiation of central Treg cells (cTreg) in secondary lymphoid tissues into effector Treg cells (eTreg) in the inflamed tissue. The requirement of the TCR signal and other cues in NLT Treg cells that reside in specific niches over extended periods of time needs to be determined and likely depends on the anatomical niche that might then also drive a distinct functional specialization of NLT Treg cells.

Figure 2

Heterogeneity of Treg cells in NLTs. Treg cells are heterogeneous and the NLT milieu is likely an important determinant of this heterogeneity. However, it is unclear whether specific hard-wired subsets of Treg cells are selectively recruited from SLOs to distinct NLTs (selection model) or whether Treg cells that enter a given NLT are locally instructed to adopt specific properties and specialize according to a niche specific program (instruction model). Alternatively, some degree of imprinting might occur in SLOs during priming and further commitment of Treg cells to certain tissue specific properties might then take place in NLTs (mixed model).