Antigen‐specific Helios⁻, Neuropilin‐1⁻ Tregs induce apoptosis of autoreactive B cells via PD‐L1

Abstract

Regulatory T cells (Tregs) maintain self-tolerance and prevent autoimmunity by controlling autoreactive T cells. We recently demonstrated in vivo that Tregs can directly suppress auto-reactive B cells via programmed death ligand 1 (PD-L1) that ligated PD-1 on B cells and caused them to undergo apoptosis. Here, we asked whether this mechanism is utilized by thymus-derived natural Tregs and/or by peripheral lymphoid tissue-induced Tregs. We first demonstrated that antigen-specific PD-L1-expressing Tregs were induced in the draining lymph node of autoantigen-expressing tissue and characterized them by their lack of the transcription factor Helios and of the surface marker Neuropilin-1 (Nrp-1). Next, we established an in vitro co-culture system to study the interaction between B cells and Treg subsets under controlled conditions. We found that Nrp Treg, but not Nrp Treg suppressed autoreactive B cells, whereas both were able to suppress T-helper cells. Such suppression was antigen-specific and was facilitated by PD-L1/PD-1-induced apoptosis. Furthermore, it required physical cell contact and was MHC II-restricted, providing an explanation for the antigen-specificity of peripherally-induced Tregs. These findings identify a role for peripherally induced Helios Nrp-1 inducible Treg in controlling peripheral B-cell tolerance against tissue auto-antigens.

CD4+CD25highCD127low/-FoxP3+ Regulatory T-Cell Population in Acute Leukemias: A Review of the Literature

“…In order to isolate Tregs more precisely, molecules that could be linked only in this subset of cells have been searched for many years. For example, high expression of Helios and Neuropilin-1 has been recently described as the intracellular markers of nTregs which may also be helpful [ 50 ]. nTregs are produced from CD4 + thymocytes by a stimulation of the TCR receptor with autoantigens [ 51 , 52 ].…”

METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma

“…According to molecular markers, Tregs fall into two major categories: resting/naïve Treg (rTreg, FOXP3 lo CD45RA + CD25 lo ) and effector/activated Treg (eTreg, FOXP3 hi CD45RA − CD25 hi ) (Ohue and Nishikawa, 2019). Effector/activated Treg has a strong immunosuppressive function and inhibits anti-tumor immunity through various molecular mechanisms, such as the regulation of the immune checkpoint molecules (Kamada et al, 2019), induction of apoptosis for immune effector cells (Gotot et al, 2018), and production of immunosuppressive cytokines (Collison et al, 2007). It has been reported that inhibition of Nr4a suppresses tumor progression via weakening Treg-mediated immune tolerance (Hibino et al, 2018).…”

Super-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications

“…However, mouse Treg lacking PD-1 were shown to be activated and have high suppressive potential ( 156 ), which underlines the necessity for further studies of this axis in human Treg. Additionally, human CD4 + Treg express PD-L1 in response to IL-7 ( 154 ) and induce apoptosis in PD-1 + Tconv ( 157 ) and autoreactive B-cells ( 158 ). As CTLA-4 has an important role in Treg function and increased degradation of CTLA-4 as present in LRBA deficiency is associated with high levels of Treg apoptosis, stabilizing strategies for sustained or increased CTLA-4 expression may also improve human Treg survival ( 159 , 160 ).…”