The mouse model of cytomegalovirus infection has been extensively studied. Accumulating data have demonstrated the critical roles of both NK cells and CD8+ T cells in the control of the infection. However, it is now clear that other subsets of cells such as innate lymphocytes play a crucial role during the immune response to viruses. We recently identified two unique populations, salivary gland NK cells and non- classical CD8+ T cells, contributing to the immune response to MCMV. Using mice deficient in classical CD8+ T cells, our preliminary data suggest that a non-classical CD8+ T cell subset expand and recognize specifically MCMV. Interestingly, these mice are resistant to the infection suggesting a critical role for the non-classical CD8+ T cells. We also characterized a unique NK cell subset present in the salivary glands of the host, a site of MCMV latency. This population of resident salivary gland NK cells has limited effector functions suggesting that CMV latency in the SMG could result from inadequate NK cell effector responses. The goal of this application is to determine the nature of these innate-like cells, determine their contributions to the immune response to MCMV infection, and manipulate their responses in order to reverse latency. We will take advantage of tools and mice developed in the previous funding period as well as new reagents from collaborators.
In Specific Aim 1, we will characterize the non-classical CD8+ T cells, identify their restricting element, and determine their role during viral infection. In Specfic Aim 2, we will examine the immune response of MCMV infected mice deficient in salivary gland NK cells or deficient in IL-10 producing NK cells further elucidating the role of this unique innat subset. In this Aim, we will also attempt to reverse the hyporesponsive phenotype of salivary glands NK cells. We believe our studies on this relatively unexplored research area will expand our current knowledge of innate-like immune cells and provide insights into strategies to restore adequate immune functions during latency.

Public Health Relevance

Human cytomegalovirus (HCMV) is a herpesvirus that infects 60 - 90% of populations. Reactivation of CMV in immunocompromised individuals and neonates can be life threatening. Using a variety of approaches, we propose here to characterize and determine the contribution of non-classical T cells and Natural Killer cells during CMV infection. This proposal has the potential to significantly improve our understanding of the immune response to viruses. In addition, the experiments proposed can potentially lead to immune intervention to reverse CMV latency.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Innate Immunity and Inflammation (III)
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Miller, Lara R
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Brown University
Schools of Medicine
United States
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