Regulation of Anti-viral CD8+ T Cells in the Liver

Krueger, Peter, Microbiology - Graduate School of Arts and Sciences, University of Virginia
Hahn, Young, Department of Microbiology, University of Virginia

The liver is a unique organ in that its immune repertoire promotes a tolerogenic environment in response to continuous exposure to immunogenic material arriving in the intestinal blood. This hyporesponsive state leaves the liver vulnerable to chronic infections, such as HCV. Impaired T cell responses correlate strongly to HCV persistence; however, little is known about the cellular and molecular mechanisms contributing to T cell dysfunction. We demonstrate that during hepatotropic viral infection, liver-resident CD103+ DCs upregulate costimulatory receptors and present Ag to induce effective anti-viral CD8+ T cell responses. Furthermore, virally infected Batf3-/- mice, which lack CD103+ DCs in the liver, exhibit a three-fold reduction in the proliferative response of Ag-specific CD8+ T cells. Limiting DC migration out of the liver does not significantly alter CD8+ T cell induction to viral infection, indicating that CD103+ DCs initiate CD8+ T cell responses in situ. Moreover, we examine local arbiters of CD103+ DC activation during hepatotropic viral infection. The liver maintains two independent group 1 ILC subsets, CD49b+ natural killer (NK) cells and CD49a+ ILC1. Liver-resident CD49a+ ILC1 constitutively express high levels of the inhibitory receptor NKG2A, suggesting they are contributing to liver immune tolerance. Viral infection in the NKG2A-/- mouse exhibits a sustained increase in the proliferative response of both adoptively transferred and endogenous anti-viral CD8+ T cells. NKG2A-/- CD49a+ ILC1 express elevated levels of IFNγ, a proinflamatory mediator of DC maturation, and liver-resident CD103+ DCs isolated from NKG2A-/- mice are capable of priming anti-viral CD8+ T cells to a greater degree than their wild-type counterparts. In summary, we demonstrate for the first time that liver-resident CD103+ DCs are the major APCs supporting anti-viral CD8+ T cell priming directly within the liver parenchyma, and that NKG2A+CD49a+ ILC1 dampen DC activation by limiting IFNγ production via NKG2A signaling. Taken together, these data help elucidate how the liver suppresses anti-viral immune responses and raises the possibility for an exciting therapeutic approach for developing next generation vaccines, i.e. targeting Ag to hepatic CD103+ DCs while inhibiting ILC1 NKG2A signaling in order to induce a more robust and sustainable CD8+ T cell response to hepatotropic viral infection.

PHD (Doctor of Philosophy)
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