Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Abstract

The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R–associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2–dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.

CD83 orchestrates immunity toward self and non-self in dendritic cells

“…The overactive phenotype observed in CD83-cKO DCs is also characterized by increased IRAK1 expression levels, which points toward an enhanced TLR signaling capacity. Interestingly, previous reports demonstrated that sCD83 also alters TLR signaling by binding to MD-2 on human monocytes, resulting in a long-lasting degradation of IRAK1 and subsequent induction of tolerogenic mechanisms (57). Likewise, CD83 on DCs could negatively modulate the TLR pathway either in cis or in trans, which would account for exaggerated inflammatory immune responses in CD83 ΔDC animals.…”

CD83 expression is essential for Treg cell differentiation and stability

“…Recently, first insights regarding CD83-mediated signaling events were published (48). This study reported that on monocytes sCD83 binds to the TLR4/MD-2 complex and alters the signaling cascade by rapidly degrading IRAK-1.…”

The CD83 Molecule – An Important Immune Checkpoint

“…However, this self-interaction is not sufficient to explain the regulatory effects of sCD83 on monocytes (68), which -in contrast to DCs -do not express mbCD83 in the steady state (32). Thus, a recent study elucidated the impact of sCD83 on monocytes by demonstrating sCD83 binding to MD-2 and the TLR4 complex (69). The authors suggested that upon binding to MD-2, sCD83 initiates an anti-inflammatory TLR-signaling cascade leading to long-term depletion of IRAK-1, which causes unresponsiveness to further TLR stimulation.…”