Current Research and Scholarly Interests
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 produce certain effector molecules, such as CD40-ligand (CD154) and IFN-gamma compared to these cells in adults due to both reduced gene transcriptional and impaired signals that lead to gene transcription. Recently, we have shown that these limitations apply to physiological T-cell activation, e.g., using allogeneic dendritic cells. Defining the molecular mechanisms for decreased IFN-gamma production by neonatal CD4 T cells is a current focus.
We have also found that recent thymic emigrants, which predominate in the newborn and young infant, are less able to differentiate into T helper 1 cells, which produce IFN-gamma. These studies required the development of a novel marker for recent thymic emigrants (RTEs) of the CD4 T-cell lineage in humans. Using a combination of approaches, we have identified protein tyrosine kinase 7 (PTK7) as such a marker. In progress are to studies to define the role of PTK7, an orphan member (no known ligand) of the receptor tyrosine kinase family, in T-cell development and immunity, and to determine how this marker can be used to follow the output of recent thymic emigrants in health and disease. We are also interesed in determining the molecular mechanisms for the reduced RTE function and to what extent these mechanisms are shared by neonatal CD4 T cells and CD4+CD8-CD3+ thymocytes, the immediate precursors of antigenically naive CD4 T cells.
We have also found that limitations in T-cell immunogenicity to viruses and viral vaccines extend beyond the neonatal period to childhood. These studies highlight a need to develop more potent vaccines to overcome developmental and other factors, such as genetic inheritance, in mounting adaptive immunity. With this as an ultimate goal, we are examining the ability of a novel adjuvant, cationic liposome DNA complexes (CLDC)(Juvaris Biotherapeutics), to induce durable CD4 and CD8 T-cell immunity and humoral immunity to influenza A. The molecular and cellular components of the innate immune system that are required for immunogenicity are of particular interest. Our preliminary results in mice suggest that the CLDC adjuvant will be substantially more robust than any adjuvants currently approved for clinical use or in clinical trials.
In collaboration with Dr. Neal Boerkoel, University of British Columbia, we are defining the mechanism of T-cell lymphopenia in genetic deficiency of SMARCAL1, a protein that may play a novel role in PolII gene transcription using T cells from patients with SMARCAL1 deficiency (Schimke immuno-osseous dysplasia) as well as SMARCAL1 knockout mice. We hypothesize that the peripheral T-cell lymphopenia is due to attenuation of transcriptional efficiency for multiple genes required for T-cell development and peripheral homeostasis, e.g., cytokines and cytokine receptors.
