Grant: $445,000 - Department of Health and Human Services - May. 29, 2009
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Award Description: Protective immunity depends on memory CD4 T cells generated during initial encounter with pathogen. Naïve CD4 T cells respond vigorously to influenza (Flu) virus, expanding and differentiating into a large effector population that participates in Flu clearance indirectly by driving B cell antibody production and directly by acting in the infected lung. Once generated, CD4 T effector cells migrate to the lung, virus is cleared rapidly and the CD4 effector population just as quickly contracts both in the lung and elsewhere, leaving memory CD4 T cells in peripheral sites. Contraction is also necessary to limit CD4 effector-mediated immunopathology in the lung, but the factors responsible for contraction are unknown. Key to immune clearance of Flu in a primary infection is the generation of a sufficiently large population of highly active effector T cells that can particpate in clearing the billions of viruses in lung epithelial cells Infection leads to high levels of Flu antigen (Ag) presentation and dramatic stimulation of the innate immune cells via recognition of viral RNA. Our hypothesis is that these two factors drive the extensive expansion of virus-specific T cells and program them for contraction. Understanding the factors that regulate the contraction phase, should give us insights into how to prevent immunopathology in immune response to respiratory pathogens and to develop vaccine strategies that modulate what CD4 T cells survive to memory.
Project Description: We have started experiments in Aim 1 to determine whether in vivo contraction of CD4 effectors is influenced by recognition of flu Ag (AICD) and/or self-MHC Class II. We will measure the degree of apoptosis, ex vivo before and after additional exposure to Ag, in the highly differentiated CD4 effectors from the lung. We will compare this level of cell death with that seen in the less differentiated effectors from the secondary lymphoid organs [spleen and lymph nodes (LN)]. We will transfer both in vitro and in vivo generated effectors to a) Ag free (uninfected) hosts and Class II deficient hosts infected with the same virus, or hosts infected with irrelevant virus (inflammation without Ag), or b) to hosts receiving APCs pulsed with varying Ag doses.
Jobs Summary: We have hired one Postdoctoral Fellow (Alison Swaims) (100%) who is now responsible for carrying out the experiments in Aims 1 and 2 with the aid of the Reearch Assistant. We have also hired a Research Assistant (Katie Huang) (100%) will provide critical technical help to support all aspects of the studies described. She is responsible for breeding and screening mice, titering and aliquoting cytokine and Ab reagents, running ELISA assays of cytokines, preparing media and cytokines and analyzing cells by flow cytometry, to enumerate the donor cells and detect cell death. Her duties include coordinating preparation of all key reagents and analysis of histological samples. (Total jobs reported: 2)
Project Status: Less Than 50% Completed
This award's data was last updated on May. 29, 2009. Help expand these official descriptions using the wiki below.