This proposal describes a 5-year training program for the development of an academic career in allergy-immunology and basic immunology research. The principal investigator is an NRSA postdoctoral fellow with attending physician privileges within the allergy-immunology section of the University of Pennsylvania. This award will engender the opportunity to develop the expertise necessary to become a successful clinician-scientist. His research interest is in innate and induced mechanisms that directly influence adaptive immunity. He has spent over two years in the laboratory of Dr. Laurence Turka, the sponsor of this application, working to define the immune functions of T cell expressed Toll-like receptors. Dr. Turka has trained numerous postdoctoral fellows and graduate students, and is a senior investigator in the areas of T cell tolerance and transplantation immunology. In addition, an advisory committee of clinician-scientists and immunologists will provide scientific and career development guidance. Penn provides a rich intellectual environment and has many resources to facilitate this work and the career development of the applicant. Research will focus on the function of T cell expressed Toll-like receptors (TLRs). TLRs are a major class of pattern recognition receptors, and the triggering of these receptors on antigen-presenting cells is critical for the innate immune response. Recent work in Dr. Turka's lab, and others, has demonstrated TLR expression in mouse and human T cells. The function of T cell TLRs has received limited, but increasing, attention. Our data show that mouse CD4(+) T cells selectively express TLR3 and 9 upon activation, and treatment with the respective ligands promotes T cell survival, activates NF-kB, and increases Bcl-xL expression. In this proposal, Aim #1 will use a focused approach of in vitro stimulation coupled with in vitro assays and in vivo adoptive transfer studies to test the hypotheses that T cell TLR stimulation using specific ligands modulates costimulatory molecule receptor expression, IL-6 production, Th17 skewing, abrogation of T regulatory cell-mediated suppression, and memory formation and persistence.
Aim #2 will turn to in vivo models using the immune response to infection and allogeneic organ transplantation to test the hypotheses that T cells require MyD88 and MyD88-dependent signaling for optimal adaptive responses. Defining how T cell TLR stimulation and MyD88 signaling may influence T cell effector function will add to the growing body of knowledge regarding innate-adaptive crosstalk in host defense. Conceptual advances in this field of study have the potential to change the way we prevent and treat human illness, including cancer, infectious disease, and allergic disorders.
|Traum, Daniel; Timothee, Patricia; Silver, Jonathan et al. (2012) IL-10-induced gp130 expression in mouse mast cells permits IL-6 trans-signaling. J Leukoc Biol 91:427-35|
|LaRosa, David F; Stumhofer, Jason S; Gelman, Andrew E et al. (2008) T cell expression of MyD88 is required for resistance to Toxoplasma gondii. Proc Natl Acad Sci U S A 105:3855-60|