Algorithms derived from measurements of short-peptide (8-10 mers) binding to class I MHC proteins suggest that the binding groove of a class I MHC protein, such as K b , can bind well over 1 million different peptides with significant affinity (<500 nM), a level of ligand-binding promiscuity approaching the level of heat shock protein binding of unfolded proteins. MHC proteins can, nevertheless, discriminate between similar peptides and bind many of them with high (nanomolar) affinity. Some insights into this high-promiscuity/high-affinity behavior and its impact on immunodominant peptides in T-cell responses to some infections and vaccination are suggested by results obtained here from testing a model developed to predict the number of cell surface peptide-MHC complexes that form on cells exposed to extracellular (exogenous) peptides.
Recall responses by memory CD8 T cells are impaired in the absence of CD4 T cells. Although several mechanisms have been proposed, the molecular basis is still largely unknown. Using a local influenza virus infection in the respiratory tract and the lung of CD4−/− mice, we show that memory CD8 T cell impairment is limited to the lungs and the lung draining lymph nodes, where viral antigens are unusually persistent and abundant in these mice. Persistent antigen exposure results in prolonged activation of the AKT-mTORC1 pathway in antigen-specific CD8 T cells, favoring their development into effector memory T cells (TEM) at the expense of central memory T cells (TCM), and inhibition of mTORC1 by rapamycin largely corrects the impairment by promoting TCM development. The findings suggest that the prolonged AKT-mTORC1 activation driven by persistent antigen is a critical mechanism underlying the impaired memory CD8 T cell development and responses in the absence of CD4 T cells.
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