Protective immunity depends on memory CD4 T cells generated during initial encounter with pathogen. Naive 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 in the lung. Once generated, CD8 and 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. The contraction is necessary to limit CD4 effector-mediated immunopathology in the lung, but the factors regulating contraction are as yet unknown. Flu viruses replicate in lung epithelial cells, generating billions of viruses leading to high levels of Flu antigen (Ag) presentation and as well to dramatic stimulation of the innate immune cells via recognition of viral RNA. We postulate that these innate events result in secretion of inflammatory cytokines, including TNF and IL-6, and that these factors act on the small initial population of CD4 T cells specific for Flu, to drive a complex program of response that includes both extensive expansion and differentiation to effectors as well as their commitment to die when they re-encounter Ag in the lung and periphery. We have developed a model in which we can study CD4 contraction, by transferring an easily identified "indicator" population of Flu-specific naive CD4 T cells from T cell receptor transgenic mice into a host mouse that we then infect with Flu. This allows us to visualize the contraction phase by enumerating effectors in the lung at the peak of their response and just after contraction a few days later. We will ask several key questions to evaluate our hypothesis. First we will ask if Flu Ag, expressed at the initiation of contraction, is necessary to induce the process of deletion of CD4 effectors via Ag-induced cell death. Second will ask if inflammatory cytokines, TNF and IL-6, elaborated as a result of infection, are acting to program both the effective T cell response and the contraction phase. Third we will ask if they accomplish this programming by increasing responding CD4 T cell production of IL-2 and IL-21. Identifying the factors that regulate the contraction phase should provide better understanding of the correlates of protective immunity and suggest future targets for manipulating immunopathology and memory generation. These results will help improve design of vaccines that are more effective in combating immunity but that avoid the consequences of immune-mediated pathology.

Public Health Relevance

Infection with viruses and bacteria generate vigorous T cell immune responses that help destroy the infectious agent and also usually lead to long term immunity, so a subsequent infection will be combated swiftly and effectively. This immunity is mediated by so-called memory T cells. It is a particular importance that we learn how to best generate memory T cells. When new strains of a virus like influenza emerge, the other major kind of immunity we have, mediated by Ab, is no longer effective because the virus has changed to evade the Ab, This escape can lead to dangerous epidemics or pandemics, like the 1918 "Spanish" influenza that killed many millions, so we must depend on T cell memory. The process of memory T cell generation is not well understood. During response a very large population of T cell effectors is formed, and in the case of influenza, many of these go to the lung and attack infected cells. Once virus is gone, these "contract" leaving behind memory T cells, mostly in lymphoid organs like the spleen. In this project we will determine how this process of contraction is regulated, so that we can learn how to design vaccines that can achieve the best T cell memory.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense Study Section (IHD)
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Hauguel, Teresa M
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University of Massachusetts Medical School Worcester
Schools of Medicine
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