Neonatal Immunity and Recent Thymic Emigrants

A long-standing interest is to understand the cellular and molecular basis for this vulnerability of the human neonate to infection with intracellular pathogens that require T helper 1 (Th1) cells [CD4 T cell producing interferon-gamma (IFN-gamma)] for effective immune control. We have previously shown that CD4 T cells of the newborn have a unique limitation in the ability to transcribe mRNAs encoding certain effector molecules, such as CD40-ligand (CD154) and IFN-gamma compared to these cells in adults. These transcriptional differences are the result of both altered upstream signal transduction events in the T cells of the fetus and young infant as well as altered chromatin accessibility. Recent RNA-Seq studies indicate that these developmental differences are the result of  fetal and young infant  T cells having a unique transcriptional program that impacts hundreds of genes and multiple regulatory RNAs. This developmental transcriptional profile is likely important for the maintenance of fetal-maternal tolerance during pregnancy.

Among the many genes that are differentially expressed by CD4 T cells,  we have focused on defining the role of increased expression of protein tyrosine kinase 7 (PTK7) by fetal and neonatal CD4 T cells in immune function. We found that PTK7, which is a member of the protein tyrosine surface receptor family originally identified in colon cancer cells, is also expressed by subpopulations of CD4 T cells in later childhood and in the adult.  PTK7 surface expression by CD4 T cells in the child and adult can be used to identify recent thymic emigrant (RTE) CD4 T cells in the peripheral blood. We are now determining the biological importance of PTK7 expression by fetal and young infant CD4 T cells and RTEs in children and adults for regulation of T-cell activation and homeostasis using both RNAi and CRISPR-based approaches.