Previous studies on the MHC class-specific differentiation of CD4 + CD8 + thymocytes into CD4 + and CD8 + T cells have focused on the role of coreceptor molecules. However, CD4 and CD8 T cells develop according to their MHC class specificities even in these mice lacking coreceptors. This study investigated the possibility that lineage is determined not only by coreceptors, but is also guided by the way how MHC molecules are presented. MHC class II molecules possess a highly conserved Cys in their transmembrane domain, which is palmitoylated and thereby associates with lipid rafts, whereas neither palmitoylation nor raft association was observed with MHC class I molecules. The generation of CD4 T cells was impaired and that of CD8 T cells was augmented when the rafts on the thymic epithelial cells were disrupted. This was due to the conversion of MHC class II-specific thymocytes from the CD4 lineage to CD8. The ability of I-A d molecule to associate with rafts was lost when its transmembrane Cys was replaced. The development of DO11.10 thymocytes recognizing this mutant I-A dm was converted from CD4 to CD8. These results suggest that the CD4 lineage commitment is directed by the raft-associated presentation of MHC class II molecules.Key words: CD4 T cell . Lipid rafts . MHC class II molecule . Thymic selection Supporting Information available online IntroductionThe ab T cells differentiate from immature CD4 + CD8 + doublepositive (DP) thymocytes to mature CD4 + and CD8 + singlepositive (SP) T cells in the thymus. This differentiation is achieved through TCR signaling that follows the engagement with self-MHC peptide complexes. The resulting CD4 and CD8 T cells possess MHC class II-specific TCR and MHC class I-specific TCR, respectively, which is consistent with MHC binding specificities of the coreceptors they express. The exact mechanism by which the DP thymocytes are committed to the appropriate T-cell lineage is not yet clear.Earlier investigations on CD4 versus CD8 lineage commitment in the thymus have focused on the roles played by coreceptor molecules. Robey et al. [1] proposed the presence of an instructive signal for CD8 T-cell development and demonstrated that constitutive CD8 expression induces substantial increase in the CD8 lineage commitment, while it has no apparent effect on CD4 96lineage commitment. The instructive model is supported for CD4 T-cell development as well, by experiments in which transgenic chimeric molecules consisting of the CD8a extracellular domain and transmembrane (TM) of CD4 or CD8 and the cytoplasmic domain of CD4 were shown to induce CD4 T cells expressing MHC class I-specific TCR [2,3]. The identification of a defect that impairs only CD4 T-cell development also supports the instructive model [4]. These observations collectively suggest that the coreceptors instruct thymocytes to differentiate into either CD4 or CD8 T cells by initiating qualitatively distinct signals. However, the functional differences between the CD4 and CD8 are mostly quantitative, i.e. more Lck molecu...
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