GARP as safeguard of the regulatory phenotype. (A) Qualitative (lineage-specific) and quantitative (dose-effect) differences in FOXP3 expression in human helper T cells (Th; upper panel) and regulatory T cells (Treg; lower panel) are due to lineage-specific methylation of the respective loci (indicated by black dots) and thus the expression of the genes FOXP3 and GARP. In human Treg cells, a positive feedback loop has been found between GARP and FOXP3; this feedback loop is interrelated with the FOXP3-enhancing molecules indicated. Phosphorylation of LGALS3 (indicated by a P) has been reported to be essential for the FOXP3-regulating function [21]. GARP is a receptor for LAP/latent TGF-β [26,27]. T-bet (T-box expressed in T cells), GATA3 (GATA-binding protein 3), RORγ (retinoic-related orphan receptor gamma) represent transcription factors of Th1, Th2, and Th17 cells. (B) Implications for human and murine T cells, respectively, of the autocrine and paracrine effects of GARP and Nrp1 surface-bound LAP/latent TGF-β after activation of TGF-β. The TGF-β signature phospho-SMAD2 (pSMAD2) has been observed in human (GARP+) and murine (Nrp1+) Treg cells. Paracrine effects include the generation of infectious tolerance. (C) Structural composition of the LAP/latent TGF-β binding proteins Nrp1 and GARP (LRR, leucine-rich repeat domain; CUB, complement subcomponents C1r/C1s domain; F5/8 coagulation factor domain; MAM, meprin, A5, and receptor protein-tyrosin phosphatase μ domain; TM, transmembrane region; L, leader peptide). NIP (Nrp1 interacting protein) is a Nrp1 binding protein involved in the regulation of Nrp1-mediated signaling as a molecular adapter [48].