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.