T cell immunity is crucial to control viral infection and prevent persistence. However, T cell functions are rapidly aborted during persistent infection, preventing viral clearance. Mounting evidence indicates that CD4 T cell helper responses are required to sustain immune competence and that the loss of CD4 T cell function is a key event permitting viral persistence. Many of the functional characteristics of CDS T cell exhaustion (failure to sustain activity, proliferate, develop memory) can potentially be explained by the loss of CD4 help. Despite immune exhaustion some persistent viral infections are eventually resolved via unknown CD4 T cell dependent mechanisms, suggesting that CD4 T cells retain helper function during viral persistence. Recently, we discovered that upregulation of IL-21 by CD4 T cells is absolutely required to sustain antiviral immunity and resolve an established persistent viral infection. The goal of this application is to understand how CD4 T cell help is altered during viral persistence and ultimately to identify the IL-21 mediated mechanisms that sustain immunity. To achieve this goal we will use the mouse model of lymphocytic choriomeningitis virus (LCMV) infection to explore virus-specific CD4 T helper differentiation during viral persistence and how IL-21 directs this developmental program. Next, we will define the mechanism whereby IL-21 simultaneously suppresses CD4 T cell mediated immunopathology and sustains CDS T cell immunity to resolve persistent viral infection. These studies will investigate a novel mechanism of CD4 T cell help during viral persistence (at a time when CD4 T cell function was previously considered lost) and will be the first to identify the immune components that resolve an established persistent viral infection. It is important to identify the mechanisms that alternatively sustain and suppress antiviral immunity to develop therapies to restore T cell function and potentially cure persistent infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-BDP-I (J4))
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Miller, Lara R
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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