Infection with a live pathogen generates an impressive T cell effector response that that clears virus and results in generation of memory CD4 and CD8 T cells as well long-lived B cells that make antibody to pathogen. Each of these arms of the immune response can provide potent protection against re-infection, but the most powerful immunity occurs when all components are present. Vaccine-induced immunological memory can also be a powerful tool to fight infectious diseases. Most attention has focused on inducing neutralizing antibody with much less attention given to achieving T cell immunity, even though B cell immunity can be readily thwarted by viruses and other pathogens that present rapidly changing surface proteins recognized by B cells. Many current vaccines do a poor job of eliciting CD4 T cell immunity and thus are less effective than they could be. We have analyzed the process in which CD4 effectors that are highly susceptible to apoptotic death become resting, long-lived memory CD4 T cells. We find that after influenza A virus infection, generation of CD4 memory cells is dependent on effectors recognizing the pathogen at the peak of the response. The effectors must produce the growth and survival cytokine, IL-2. This recognition of the pathogen leads to short and long- term survival of a small cohort of effectors so they can transition to memory and be maintained for months or years. Without these components little or no CD4 memory develops. Thus this step acts as a Memory Checkpoint. We propose that most memory CD4 T cells require these events to become memory and that the pathogen provides not only the antigen the CD4 T cells must recognize, but also supplies danger signals to directly activates the cells that the CD4 T cells interact with in an effective way. We also propose that the interaction of CD4 T cells with pathogen-activated antigen-presenting cells provides unique signals that drive the transition to memory that contrasts to further effector differentiation. We will test these hypotheses and define the mechanistic pathways involved. In so doing we expect to discover key requirements for CD4 memory generation that will inform development of more effective vaccines to achieve CD4 memory.

Public Health Relevance

Successful vaccination against rapidly evolving infections should induce CD4 T cell memory as well as B cell memory. Our studies indicate that the generation of CD4 T cell memory to influenza A virus infection requires viral antigen and pathogen-associate danger signal at the late effector stage of response as well as initially and that unique antigen-presenting cells are needed to induce pathways required for transition to memory. It is important to understand how effective CD4 memory is generated to design vaccines that induce CD4 memory.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunity and Host Defense (IHD)
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Kelly, Halonna R
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University of Massachusetts Medical School Worcester
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