Abstract
Signaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.
Highlights
Regulatory T cells (Treg cells), which are potent immunosuppressors, are characterized by the expression of the lineagespecification factor Foxp3.1,2 Efficient interleukin-2 receptor (IL2R) signaling is essential for the suppressive activity of Treg cells and their homeostasis
Based on the known three-dimensional structure of human CD25,27 Y129 is located in the extracellular part of the protein and probably forms a hydrogen bond with P8 that may help to stabilize a region of the CD25 protein that is in direct contact with IL-2 (Supplementary Fig. 2a)
The absolute cell numbers of CD62L−CD44+ Treg cells were comparable between WT and Cd25Y129H mice, increased percentages of CD62L−CD44+ Treg cells were observed in Cd25Y129H mice (Fig. 3h). These results indicated that reduced expression of CD25 impaired the maintenance of CD62L+CD44− Treg cells, regardless of whether they resided in lymphoid tissues or nonlymphoid tissues (NLTs), a finding that is consistent with previous reports showing that interleukin-2 receptor (IL-2R) signaling is required for cTreg cell homeostasis.[31,32]
Summary
Regulatory T cells (Treg cells), which are potent immunosuppressors, are characterized by the expression of the lineagespecification factor Foxp3.1,2 Efficient interleukin-2 receptor (IL2R) signaling is essential for the suppressive activity of Treg cells and their homeostasis. These findings have been inferred from germline knockout animal model,[3,4] neutralizing antibody,[5,6] adoptive cell transfer,[7,8] and in vitro studies.[9,10] efforts to evaluate the requirements for IL-2R signaling in Treg cell development, peripheral homeostasis, and suppressive function have been hampered by the emergence of massive lymphocyte proliferation and lethal autoimmunity in mice carrying germline or cell type-specific mutations affecting IL-2R signaling components.[4,11,12,13] some of the initial studies addressing. It is well established that IL-2 maintains peripheral Treg cells, it is not fully understood at which stage and to what degree IL-2R signaling contributes to the induction of Foxp[3] expression and
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