Human repair‐related Schwann cells adopt functions of antigen‐presenting cells in vitro

Abstract

The plastic potential of Schwann cells (SCs) is increasingly recognized to play a role after nerve injury and in diseases of the peripheral nervous system. Reports on the interaction between immune cells and SCs indicate their involvement in inflammatory processes. However, the immunocompetence of human SCs has been primarily deduced from neuropathies, but whether after nerve injury SCs directly regulate an adaptive immune response is unknown. Here, we performed comprehensive analysis of immunomodulatory capacities of human repair‐related SCs (hrSCs), which recapitulate SC response to nerve injury in vitro. We used our well‐established culture model of primary hrSCs from human peripheral nerves and analyzed the transcriptome, secretome, and cell surface proteins for pathways and markers relevant in innate and adaptive immunity, performed phagocytosis assays, and monitored T‐cell subset activation in allogeneic co‐cultures. Our findings show that hrSCs are phagocytic, which is in line with high MHCII expression. Furthermore, hrSCs express co‐regulatory proteins, such as CD40, CD80, B7H3, CD58, CD86, and HVEM, release a plethora of chemoattractants, matrix remodeling proteins and pro‐ as well as anti‐inflammatory cytokines, and upregulate the T‐cell inhibiting PD‐L1 molecule upon pro‐inflammatory stimulation with IFNγ. In contrast to monocytes, hrSC alone are not sufficient to trigger allogenic CD4+ and CD8+ T‐cells, but limit number and activation status of exogenously activated T‐cells. This study demonstrates that hrSCs possess features and functions typical for professional antigen‐presenting cells in vitro, and suggest a new role of these cells as negative regulators of T‐cell immunity during nerve regeneration.

Schwann cells and myelin in human peripheral nerve: Major protein components vary with age, axon size and pathology

“…In nerves with axon loss, other types of SCs develop that have no associated myelin or axons. During, and immediately after, Wallerian degeneration, ‘repair’ SCs, a phenotype specialised for phagocytosis and promoting axonal regeneration [12–16], become manifest. With increased time after axon loss without regeneration, Büngner band cells, with an elongated shape that extends parallel to the length of the nerve, may guide, and facilitate, the growth of regenerating axons.…”

Dissection and reconstruction of the colorectal cancer tumor microenvironment

“…Schwann cells were uncommon but present in several tumors ( Figure 3C ). Intriguingly, the Schwann cells expressed genes usually associated with APCs – a phenotype previously described as an inflammatory response in nerves 7,8 . Myoblasts/myocytes were only present in one tumor, likely from sampling submucosal muscle infiltration.…”

Schwann cells in the normal and pathological lung microenvironment

“…SCs are now known as antigen-presenting cells supporting neuron survival and preserving axons (Hartlehnert et al, 2017). For instance, recent data characterizing repair SCs revealed high levels of expression of MHC class II molecules and costimulatory and co-inhibitory molecules, including CD40, CD80, CD86 CD58 (or LFA-3), and CD276 (or B7-H3) (Berner et al, 2022). The ability of these SCs to produce both pro-and antiinflammatory cytokines and chemokines, regulate PD-L1-mediated T cell inhibition, and control the activation state of T cells suggest their functional similarities with professional antigen-presenting cells and immune regulators of T cell responses during nerve repair process (Berner et al, 2022).…”

“…For instance, recent data characterizing repair SCs revealed high levels of expression of MHC class II molecules and co-stimulatory and co-inhibitory molecules, including CD40, CD80, CD86 CD58 (or LFA-3), and CD276 (or B7-H3) ( Berner et al, 2022 ). The ability of these SCs to produce both pro- and anti-inflammatory cytokines and chemokines, regulate PD-L1-mediated T cell inhibition, and control the activation state of T cells suggest their functional similarities with professional antigen-presenting cells and immune regulators of T cell responses during nerve repair process ( Berner et al, 2022 ). SCs interaction with peripheral nerve resident macrophages may be responsible for cancer-induced pain, at least in some experimental systems ( De Logu et al, 2021 ).…”