Neonates demonstrate a transient deficiency in cell-mediated immunity that renders them particularly susceptible to intracellular infections and particularly susceptible to induction of tolerance. A central cause of poor cell-mediated immunity in babies is the failure to develop strong CD4+ T-helper-1 (Th1) responses, but the molecular basis for poor Th1 responses is not fully understood. In particular, early T cell activation events beginning with the T cell receptor (TCR) signal transduction pathways are poorly defined in neonates. Interestingly, we have found in preliminary studies that TCR signal transduction in neonatal cells differs significantly from that in adult cells. Adult recent thymic emigrants (RTEs) represent an analogous population to neonatal T cells and interestingly show a similar defect in Th1 immunity. The studies proposed here will address three basic questions that arise from our observations: 1) What are the molecular differences in T cell activation between mature adult T cells and RTEs or neonatal cells? 2) What, if any, biological purpose do these differences serve? and 3) What signals are necessary erase these differences and to convert RTEs into mature T cells? We hypothesize that both neonatal and RTE populations are hardwired to avoid strong Th1 responses, even beginning with their TCR signal transduction pathways. In addition we hypothesize that the immature phenotype of neonatal cells and RTEs serves to provide a window in time in which autoreactive clones may easily be made tolerant in the periphery. Finally, we hypothesize that signals received in the periphery such as IL-7 receptor or Toll-like receptor signals drive maturation of RTEs. Specifically our aims are: 1) To define early activation and TCR signaling events in neonatal T cells and RTEs. For this, we will utilize recently developed phospho-flow cytometry technologies to directly visualize TCR signal transduction in single cells after physiologic stimulation. 2) To define the behavior of neonatal T cells and RTEs in animal models of tolerance. 3) To define the role of IL-7 driven homeostatic proliferation and TLR receptor signaling on maturation of RTEs.
These aims, if accomplished, will provide fundamental molecular insights into the poor cell mediated immunity of neonates and into the mechanisms of peripheral tolerance which are vital to prevent autoimmune disease.
| Bhaumik, Suniti; Giffon, Thierry; Bolinger, Derek et al. (2013) Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants. J Immunol 190:2603-13 |
| Cohen-Wolkowiez, Michael; Poindexter, Brenda; Bidegain, Margarita et al. (2012) Safety and effectiveness of meropenem in infants with suspected or complicated intra-abdominal infections. Clin Infect Dis 55:1495-502 |
| Black, Allison; Bhaumik, Suniti; Kirkman, Richard L et al. (2012) Developmental regulation of Th17-cell capacity in human neonates. Eur J Immunol 42:311-9 |
