The SLAM-Associated Protein Signaling Pathway Is Required for Development of CD4+ T Cells Selected by Homotypic Thymocyte Interaction

SummaryMHC class II-expressing double-positive thymocytes induce progression of CD4+ T cell development as efficiently as cortical thymic epithelial cells do. Because double-positive thymocytes expressing CD1d select natural killer T (NKT) cells, we investigated whether thymocyte-selected CD4+ (T-CD4) T cells require the same signaling components as NKT cells. Using bone-marrow chimeras, we found that the signaling molecules SAP, Fyn, and PKCθ were essential for T-CD4 T cell generation, whereas mutations in the Ly108 receptor, interleukin-15 receptor α, or the transcription factor T-bet had a marginal effect. Furthermore, SAP was critical for IL-4 production by T-CD4 T cells, but the PKCθ deficiency did not alter the ability of T-CD4 T cells to produce cytokines. T-bet was necessary to produce the maximum amount of IFN-γ for CD4+ T cells regardless of the selection pathway. Thus, in contrast to epithelial cell-selected CD4+ T cells, the two distinct lineages of T cells selected by thymocytes—i.e., T-CD4 and NKT cells—both utilize the SAP-Fyn-PKCθ pathway for their development and function.