Research Interests

Neonatal Immunity

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.

Recent Thymic Emigrants

The peripheral neonatal T-cell compartment is dominated by T cells that have recently emigrated from the thymus (recent thymic emigrants or RTEs) and that may have reduced immune function compared to “older” naïve T cells. Thus, decreased neonatal immunity might be due, at least in part, to impaired RTE function. To test this hypothesis we have identified a novel surface marker for human CD4 T-lineage RTEs, and have shown that RTEs found in adult peripheral blood have substantially reduced in vitro function compared to the bulk of naive CD4 T cells. We are now 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. Studies of murine RTEs in vivo are also being performed, and CD4 RTEs in these animals have similar defects as human RTEs in terms of IFN-gamma production, suggesting that these developmental limitations are fairly robust evolutionarily. We are planning studies to examine the utility of this marker for monitoring thymic CD4 T-cell output in clinical states in which thymic function may be altered.

Vaccine Adjuvants for Respiratory Viruses

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)(Colby Pharmaceutical Company), 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.

Primary Immunodeficiencies

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.

Finally, we are beginning to comprehensively evaluate the immune function with patients with known or suspected primary immunodeficiency disorders. With the support of the Jeffrey Modell Foundation, patients with a variety of genetic immunodeficiency disorders as well as acquired immunodeficiency due to anti-cytokine antibodies have been identified, and their leukocytes and plasma are being immunophenotyped for gene expression and autoantibody composition in collaboration with the Human Immunology Core and P.J. Utz's laboratory.