CD83 expression is essential for Treg cell differentiation and stability

Abstract

Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.

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

“…The same mechanism, but MARCH8-dependent, causes decreased surface MHC-II levels on cortical TECs in CD83 -/mice (9,23), resulting in defective positive selection and drastically reduced numbers of peripheral CD4 + T cells (24). Additionally, our group revealed that expression of CD83 is essential for Treg homeostasis and stability (25).…”

“…Here, we demonstrate that CD83-deficient BMDCs express elevated levels of IL-2 and IL-12 early (i.e., 6 hours) after stimulation and induce higher antigen-dependent T cell proliferation and a more proinflammatory milieu when cocultivated shortly after TLR activation. Thus, we suggest an important modulatory role of CD83 for DC homeostasis, similar to its impact on Tregs (25). Because aberrant expression of MHC-II disrupts normal DC function and CD83-deficient DCs display lower surface levels of MHC-II (37), this reduced expression may account for the increased proinflammatory phenotype of DCs derived from CD83 ΔDC mice.…”

The CD83 Molecule – An Important Immune Checkpoint

“…Compared to wildtype mice, these cKO mice showed a reduced percentage of Foxp3 + Tregs and an increased pro-inflammatory phenotype, which became even more prominent in aged mice. Moreover, elevated levels of autoantibodies against nuclear antigens were detected in the sera of young mice compared to the respective wt controls (38). This indicates an imbalance of the immune tolerance in Treg-specific CD83-deficient mice.…”

“…By contrast, expanded human CD25 hi CD45RA + Tregs already reached their CD83 mRNA expression maximum 3 h after stimulation (23). Strikingly, TCRstimulation of human and murine CD4 + T cells together with transforming growth factor beta (TGFβ) not only resulted in the expected differentiation into CD4 + CD25 + Foxp3 + iTregs but also in a sustained and stable CD83 expression (37,38). In addition, immunofluorescence microscopy revealed CD83 to colocalize with CD25 on those cells (37).…”

“…Regarding the demonstrated induction of iTregs by CD83 expression in murine naïve T cells the study showed that in vitro-differentiation of naïve CD4 + T cells from Foxp3-specific cKO mice resulted in strongly reduced numbers of Foxp3 + iTregs. Interestingly, this intrinsic loss of CD83 expression in Foxp3 + iTregs lead to reduced expression levels of Treg-specific differentiation markers and induced expression of inflammatory cytokines (35,38).…”