Development and Function of Thymocyte-Selected CD4 T Cells.

Abstract

CD4 T cells play important roles in adaptive immune responses. Conventional understanding of CD4 T cell development is that the MHC class II molecules on cortical thymic epithelial cell are necessary for selection, as shown in mouse models. However, increasing evidence suggests that CD4 T cell selection mediated by hematopoietic cells such as thymocytes also occurs in humans as well as in mouse models. Thymocyte-selected CD4 T cells (T-CD4 T cells) are shown to be different from epithelial cell-selected CD4 T cells (E-CD4) in many aspects including developmental requirements and functional characteristics.

In this study, the strength of TCR signaling necessary for T-CD4 T cell development and role of T-CD4 T cells during bacteria infection was investigated. In contrast to E-CD4 T cells, T-CD4 T cells were selected more efficiently when TCR signaling was weakened. In addition, T-CD4 T cell development relied on the presence of the promyelocytic leukemia zinc finger protein, a transcription factor essential for invariant NKT cell generation. The distinct developmental process mediated by thymocytes resulted in T-CD4 T cells possessing the suppressive function. Instead of promoting host immunity as E-CD4 T cells do, T-CD4 T cells suppressed anti-Listerial responses, evidenced by the reduced frequency and cytotoxicity of Listeria-specific CD8 T cells during both the primary and the memory immune response. Studies in this dissertation revealed the novel suppressive function of T-CD4 T cells, which is most likely caused by the differential signaling delivered during thymocyte-thymocyte interactions in the thymus.