Abstract
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
Highlights
Regulatory T cells (Treg cells) expressing the lineage-defining transcription factor forkhead box protein P3 (Foxp3) form an integral part of the adaptive immune system and function to prevent unwanted immune responses [1,2]
We observe that the expression of miR-181a/b-1 in peripheral Treg cells is much lower when compared to thymocytes; our study implies that peripheral Treg-cell effector function is imprinted during intrathymic differentiation
Using a recombination activating gene 1–green fluorescent protein (Rag1GFP) knock-in allele to discriminate between nascent and mature thymus-resident or recirculating Treg cells, we found that frequencies and absolute numbers of de novo generated Rag1GFP-positive Treg cells were reduced by 2- to 3-fold in miR-181a/b-1−/− mice when compared to control, indicating that expression of miR-181a/b-1 is required for normal Treg-cell development in the thymus (Fig 1A)
Summary
Regulatory T cells (Treg cells) expressing the lineage-defining transcription factor forkhead box protein P3 (Foxp3) form an integral part of the adaptive immune system and function to prevent unwanted immune responses [1,2]. Some Treg-cell precursors are found within a cluster of differentiation (CD) 4 single-positive (SP) Foxp3−, glucocorticoidinduced tumor necrosis factor receptor-related protein high (GITRhi), CD25+ population [8] These cells are the first precursors generated in double transgenic TCR/cognate-antigen mouse models [9,10]. An additional CD4SP Foxp3+CD25− Treg-cell precursor has been described [11] These cells are phenotypically less mature than tTreg cells, are generated with similar kinetics as tTreg cells upon induction of T-cell development in vivo, and efficiently become tTreg cells in vitro and in vivo [10,11]. Reduction of major histocompatibility complex (MHC) ligand levels on medullary thymic epithelial cells rescued autoreactive T cells from clonal deletion but resulted in a concomitant increase in Treg-cell development, suggesting that at least some tTreg cells are generated through weaker TCR signals than those inducing clonal deletion [16]
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