Influenza viruses are NIAID category C pathogens that represent a serious world-wide health problem for elderly and immune-compromised people every year. Human infections with a highly pathogenic strain of avian influenza virus have recently become the focus of intense international concern, since pandemic infections have the potential to cause colossal mortality rates in healthy adults. Cytotoxic T cells are an important defense mechanism that can promote viral clearance from the lungs. But the protection lasts only a few months even though large numbers of virus-specific CDS T cells persist in the organs of the infected animals several years. Increasing evidence suggests that T cell location during secondary viral challenge may be an important factor in protection, but the mechanisms that control T cell retention near the site of viral infection are poorly understood. Our preliminary data show that processed viral antigens are presented in v/vofor several weeks (and maybe months) after pulmonary influenza virus infection. Based on these data we postulate that chronic stimulation with antigen helps maintain activated CDS T cells near the site of viral infection.
Two specific aims will be used to test this hypothesis.
AIM 1. To investigate how residual viral antigens influence local CDS T cell migration in the lungs and MLN after pulmonary influenza virus infection. Transfer studies will determine the full duration and anatomical location of antigen presentation in influenza infected mice. In addition, in situ class I MHC tetramer analysis will be used to localize antigen-specific CDS T cells in the tissues and visualize their interactions with other accessory cells and/or adhesion molecules that may impede their migration.
AIM 2. To investigate whether CD11c+ antigen presenting cells (APCs) are required for presentation of residual viral antigens to T cells after influenza virus infection. Mice that express the human diphtheria toxin receptor under the control of the CD11c promoter (CD11c-DTR) will be used to make chimeric mice with ablation-sensitive CD11 c+ APCs. These mice will be used to determine whether T cell activation in the lungs is prevented when antigen-bearing APCs are depleted in vivo. ? ? ?
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