Following viral challenge, failure of the immune system to control and eliminate virus results in chronic infection. In many chronic viral infection, viral persistence drives the loss of T cell function, termed "exhaustion". T cell exhaustion represents an obstacle to the treatment and clearance of many viral infections and tumors. A complex genetic program regulates the expression of inhibitory receptors by exhausted T cells, and signaling through these receptors mediates their poor anti-viral function. CD4 T cells play a key role in providing help, through direct cell-cell interactions, or through the secretion of solule factors, to maintain the anti-viral function of CD8 cells during chronic viral infection, allowing or improved viral control. The objective of this study is to determine the cellular and molecular mechanisms for CD4 help provided to CD8 T cells during chronic viral infection. The well- characterized lymphocytic choriomeningitis virus (LCMV) will be used to investigate the contribution of CD4 T cells following severe CD8 T cell exhaustion in chronically infected mice. These experiments will be used to determine the functional characteristics and relevant CD4 T helper lineage of cells that provide optimal help to CD8 T cells during chronic LCMV infection. Furthermore, the functional and molecular program that regulates the restored anti-viral function of CD8 T cells that receive help from CD4 T cells during chronic infection will be investigated.
We seek insight into better preventative vaccine design and therapeutic strategies for the treatment of chronic infections and tumors. The goal of these studies is to identify key characteristics and genes involved in the improved function of T cells during chronic viral infections. Improved understanding of the factors that regulate T cell function during chronic infection will provide potential targets for therapeutic intervention.
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|Hale, J Scott; Youngblood, Ben; Latner, Donald R et al. (2013) Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity 38:805-17|