The liver evolves mechanism(s) to dampen and possibly suppress the host immunity to nonpathogenic food antigens. As a result, liver tropic viruses such as HCV establish the persistent infection in the liver due impaired CD8+ T cell responses. NK cells are highly enriched in the liver and act as innate defense to viral infection. Following conjugation between NK cells and target cells, NK cells are activated and express NK activating/inhibitory receptors to trigger NK activity. Signaling through intimate interaction of NK activation/inhibitory receptors is critical for controlling NK activities. NK cells have been reported to play a pivotal role in linking innate immunity to adaptive immunity, particularly regulation of intrahepatic CDS* T cell responses during viral infection. We have recently established a murine model system via two different routes (i.e. IV vs SubQ) of adenovirus infection, which is an important system to dissect the mechanism for regulation of intrahepatic CD8+ T cell responses. IV inoculation predominantly delivers viral antigen to the liver while SubQ injection expresses antigen into the lymph nodes. By employing this murine model, we found that different route of adenovirus infection influence the magnitude and effector function of CDS* T cell responses. The impaired CDS* T cell responses were found in the liver of mice following IV infection. In contrast, mice infected SubQ adenovirus infection generates the effective CDS* T cell responses. In addition, NKG2A*NK cells and IL-10-producing DC are increased in the liver from IV Ad-LacZ infected mice. Intriguingly, the in vivo depletion of NK cells reversed the dysregulation of antiviral CDS* T cell responses. These results, coupled with evidence that the inhibitory function of liver NK cells, suggest a potential mechanism for NK cell-mediated in inhibition of CDS* T cell effector function via NK-DC cross-talk. In this proposal, we will characterize the effect of NK cells on affecting CDS* T cell responses and determine the mechanism for NK-mediated impairment of CDS* T cell effector function via altering DC activation. These studies may provide a useful information regarding the regulatory role of NK cell dysregulation in generation of effective CDS* T cell responses as well as new insights for immunotherapeutic strategies against viral infection.

Public Health Relevance

Viral infection in the liver often establishes persistent infection. This could be due to the failure of generating effective T cell responses to liver infection in the host. The main goal of Project 2 is to determine how liver viral infection suppresses the host T cell immunity and to identify a potential mechanism of regulation of T cell immunity via altered innate immunity.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-BDP-I)
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University of Virginia
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Dolina, Joseph S; Braciale, Thomas J; Hahn, Young S (2014) Liver-primed CD8+ T cells suppress antiviral adaptive immunity through galectin-9-independent T-cell immunoglobulin and mucin 3 engagement of high-mobility group box 1 in mice. Hepatology 59:1351-65
Moser, Emily K; Hufford, Matthew M; Braciale, Thomas J (2014) Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner. PLoS Pathog 10:e1004315
Ely, Kenneth H; Matsuoka, Mitsuo; DeBerge, Matthew P et al. (2014) Tissue-protective effects of NKG2A in immune-mediated clearance of virus infection. PLoS One 9:e108385
DeBerge, Matthew P; Ely, Kenneth H; Enelow, Richard I (2014) Soluble, but not transmembrane, TNF-? is required during influenza infection to limit the magnitude of immune responses and the extent of immunopathology. J Immunol 192:5839-51
Kim, Taeg S; Gorski, Stacey A; Hahn, Steven et al. (2014) Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism. Immunity 40:400-13
Yoo, Jae-Kwang; Braciale, Thomas J (2014) IL-21 promotes late activator APC-mediated T follicular helper cell differentiation in experimental pulmonary virus infection. PLoS One 9:e105872
Yoo, Jae-Kwang; Kim, Taeg S; Hufford, Matthew M et al. (2013) Viral infection of the lung: host response and sequelae. J Allergy Clin Immunol 132:1263-76; quiz 1277
Braciale, Thomas J; Hahn, Young S (2013) Immunity to viruses. Immunol Rev 255:5-12
Gorski, Stacey Ann; Hahn, Young S; Braciale, Thomas J (2013) Group 2 innate lymphoid cell production of IL-5 is regulated by NKT cells during influenza virus infection. PLoS Pathog 9:e1003615
Goh, Celeste; Narayanan, Sowmya; Hahn, Young S (2013) Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 255:210-21

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