Klonowski, Kim;
Sage, Leo;
Rose, David;
Fox, Julie;
Huang, Lei;
Barber, Jaime;
Tompkins, S. Mark;
Mellor, Andrew;
Tripp, Ralph
Inhibition of Indoleamine 2,3-dioxygenase (IDO) enhances the memory CD8 T cell response and modulates the immunodominance hierarchy following influenza infection (48.17)
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Media type:
E-Article
Title:
Inhibition of Indoleamine 2,3-dioxygenase (IDO) enhances the memory CD8 T cell response and modulates the immunodominance hierarchy following influenza infection (48.17)
Contributor:
Klonowski, Kim;
Sage, Leo;
Rose, David;
Fox, Julie;
Huang, Lei;
Barber, Jaime;
Tompkins, S. Mark;
Mellor, Andrew;
Tripp, Ralph
imprint:
The American Association of Immunologists, 2012
Description:
<jats:title>Abstract</jats:title>
<jats:p>The generation of heterosubtypic CD8 T cell responses is important for cross-protective immunity against unrelated strains of influenza. The need to maintain tolerance in the lung, however, limits the overall breadth and duration of CD8 T cell responses, warranting a better understanding of mechanisms of immunoregulation at this site. Influenza infection induces pulmonary expression of the tryptophan catabolizing enzyme IDO. Depletion of tryptophan results in suppression of T cell expansion or effector function, T cell anergy, or deletion. We hypothesized that ablation of IDO activity during CD8 T cell priming would enhance the subsequent CD8 T cell memory pool. To test this in vivo, we conditionally ablated IDO activity during the priming phase using the inhibitor 1-methyl tryptophan (1MT). 1MT-treated animals challenged with a lethal dose of a heterosubtypic influenza virus generated a more robust Th1 response, with enhanced migration to the lung airways. Interestingly, the immunodominance hierarchy was also shifted to favor subdominant CD8 T cell epitopes in both 1MT-treated and IDO-deficient animals, likely a result of observed decreased regulatory T cell function. While 1MT treatment did not affect cytotoxicity or viral clearance, pulmonary pathology was reduced in the absence of IDO. Together these data provide evidence that modulation of IDO activity in the context of influenza infection could be exploited in vaccine development to enhance memory CD8 T cell responses.</jats:p>