Alternative Splicing Generates Putative Soluble CD83 Proteins That Inhibit T Cell Proliferation

Abstract

CD83 is expressed on mature dendritic cells and activated lymphocytes and has been implicated to play an important role during T cell development in the thymus. In contrast, not much is known about the function of CD83 in the periphery. Soluble forms of CD83 have been detected in the serum, but neither the function nor the mechanism of how these soluble forms of CD83 are generated are fully understood. In this study, we report the identification of four different transcripts of CD83 in unstimulated PBMCs. Sequence analysis demonstrated that the longest form codes for transmembrane CD83 (CD83-TM), whereas the smaller transcripts are splice variants of full-length CD83, coding for putative soluble CD83 proteins. Stimulation of PBMCs with PHA, TNF-α, or LPS leads to the up-regulation of the full-length CD83 transcript and to a strong down-regulation of two of the three smaller transcripts. The smallest CD83 splice product can be translated efficiently into protein, and recombinant soluble CD83 shows a strong inhibitory effect on T cell proliferation in MLRs. Our results suggest that the constitutive production of soluble forms of CD83 under steady-state conditions may have an important function in regulating immune homeostasis.

CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity

“…However, stimulation of naive T cells in the presence of supernatants from CD83-transduced T cell cultures had no significant effect on the proliferative capacity (data not shown) as it was described for sCD83 (20,24,25). Additionally, CD83-transduced T cells and CD4 ϩ CD25 ϩ Treg cells lost their in vitro suppressive capacity in the absence of cell-cell contact (Fig.…”

“…Further evidence for the inhibitory function of sCD83 isoforms was shown by Dudziak and colleagues (24). They identified four different transcripts of CD83 in unstimulated PBMCs.…”

“…The largest form codes for the transmembrane CD83, whereas the smaller transcripts encode putative soluble forms and are splice variants of full-length CD83. Interestingly, the smallest CD83 splice product could be efficiently translated into protein, and this recombinant soluble CD83 isoform showed a strong inhibitory effect on T cell proliferation using MLR assays (24).…”

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

“…Although its exact function is still unknown, various independent studies using soluble forms of CD83 or employing CD83-specific RNA interference provided evidence that this surface molecule is required for efficient DC-mediated T-cell activation [14][15][16][17]19]. Furthermore, it has been shown that CD4 1 single-positive thymocyte development is impaired in CD83 (CD83 À/À ) knockout mice, resulting in pronounced reduction of peripheral CD4 1 T cells [44].…”

“…Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23].…”