TNFR2 expression is a hallmark of human memory B cells with suppressive function

Abstract

Tumor Necrosis Factor Receptor 2 (TNFR2) expression is increasingly being linked to tolerogenic immune reactions and cells with suppressor function including a subset of T-regulatory cells. B-regulatory cells play an important role in control of T-cell responsesand inflammation. Recently, we described TNFR2 as a marker for IL-10-producing B cells, a hallmark of this cell subset. Here, we demonstrate that proliferation of T cells is reduced in the presence of TNFR2 positive human memory B cells generated with TLR9 ligand, while TNFR2-and TNFR2+CD27-B cells display costimulatory activity. Our data further reveal that IL-10 secretion is characteristic of IgM+ naïve and memory B cells but suppressive activity is not restricted to IL-10: (i) the inhibitory effect of TNFR2+ switched memory B cells was comparable to that exerted by TNFR2+ IgM+ memory B cells although IL-10 secretion levels in the cocultures were lower; (ii) supernatants from TNFR2+ memory B cells failed to suppress T-cell proliferation. Based on our findings, we propose that formation of Breg is a specific characteristic of human memory B cells undergoing terminal differentiation. Our data further corroborate that TNFR2 represents a viable marker for identification of memory B cells with regulatory function.

Cytokine Receptors—Regulators of Antimycobacterial Immune Response

“…TGF-β is a multifunctional growth factor regulating cell differentiation, proliferation, migration, apoptosis, and extracellular matrix remodeling [125]. Many cell types, including macrophages, release the cytokine in a latent form that is complexed with two other polypeptides, latency-associated peptide (LAP), and latent TGF-β binding protein (LTBP) TNFR2 is only present in specific cell subpopulations, including DC, monocytes, and T cells [114][115][116][117][118][119] and after induction in a variety of peripheral B-cell subpopulations [120]. While TNFR1 typically induces cell death and chronic inflammatory mechanisms via canonical NF-κB activation, TNFR2 promotes pro-survival and reparative cascades via the activation of the phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase B (PKB/AKT) pathway and non-canonical NF-κB signaling [105].…”

“…Although TNFR1 and TNFR2 are characterized by distinct affinity to TNF-α and differential signaling pathways that lead to divergent immune effector functions, the crosstalk between the receptors may occur. The p100 and RelB proteins, overexpressed during the activation of the canonical NF-kB pathway induced by TNFR1, enter the non-canonical activation pathway induced by TNFR2, which results in cell survival and proliferation [111,120]. Numerous studies have shown that TNF plays a primary role in mounting defense mechanisms against Mtb infections [121][122][123][124].…”

Plasma extracellular vesicles bearing PD-L1, CD40, CD40L or TNF-RII are significantly reduced after treatment of AIDS-NHL

“…We then examined other molecules important for B and T cell signaling, such as CD40, CD40L, and B7-H3 (CD276), which have co-stimulatory/co-inhibitory immunoregulatory functions 36 , and are highly expressed in different types of cancers 37 . We also evaluated the expression of TNF-RII on EVs, whose expression has been linked to tolerogenic immune reactions, including a subset of T-regulatory cells 38 and IL-10-producing B cells 39 ; and EVs expressing IL-6Rα, which is of high interest since our previous work has shown that IL-6 has prognostic value as an indicator of subsequent response to AIDS-NHL treatment and survival 16 . Moreover, we also quantified plasma levels of FasL-expressing EVs.…”

Splenic Architecture and Function Requires Tight Control of Transmembrane TNF Expression

“…Whereas TNFRI is ubiquitously expressed, TNFRII expression is mainly limited to specific immune cells, including Tregs and B regulatory cells. Consequently, TNFRII has been implicated to mediate homeostatic and regulatory effects, rather than inducing inflammation [40,[45][46][47][48][49].…”