Interaction between the mouse homologue of CD99 and its ligand PILR as a mechanism of T cell receptor-independent thymocyte apoptosis

Abstract

Here, we show that the interaction between two membrane proteins, the mouse homologue of CD99 (designated D4) and its ligand, paired immunoglobulin-like type 2 receptor (PILR), is one of the major mechanisms of thymocyte apoptosis. Using the polymeric fusion protein of PILR and IgG1 (PILR-Ig), we demonstrated that D4 ligation in the absence of T cell receptor (TCR) engagement leads to the induction of apoptosis, mainly at the double-positive stage of thymocytes. This was further confirmed by a blocking study in which blocking the interaction between D4 and PILR by soluble D4 protein led to reduced apoptosis in the fetal thymic organ culture with wild type and TCR alpha(-/-) mice. Furthermore, the dissection of intracellular signaling pathway demonstrated that D4 cross-linking led to caspase activation without any change in mitochondrial membrane potential. Based on these data, we propose a mechanism for thymocyte depletion in which the interaction between D4 and PILR delivers an active signal.