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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI046709-12
Application #
8717555
Study Section
Innate Immunity and Inflammation (III)
Program Officer
Miller, Lara R
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brown University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Providence
State
RI
Country
United States
Zip Code
02912
Erick, Timothy K; Anderson, Courtney K; Reilly, Emma C et al. (2016) NFIL3 Expression Distinguishes Tissue-Resident NK Cells and Conventional NK-like Cells in the Mouse Submandibular Glands. J Immunol 197:2485-91
Anderson, Courtney K; Brossay, Laurent (2016) The role of MHC class Ib-restricted T cells during infection. Immunogenetics 68:677-91
Erick, Timothy K; Brossay, Laurent (2016) Phenotype and functions of conventional and non-conventional NK cells. Curr Opin Immunol 38:67-74
Anderson, Courtney K; Salter, Alexander I; Toussaint, Leon E et al. (2015) Role of SHIP1 in Invariant NKT Cell Development and Functions. J Immunol 195:2149-56
Guan, Jean; Miah, S M Shahjahan; Wilson, Zachary S et al. (2014) Role of type I interferon receptor signaling on NK cell development and functions. PLoS One 9:e111302
Reilly, Emma C; Thompson, Elizabeth A; Aspeslagh, Sandrine et al. (2012) Activated iNKT cells promote memory CD8+ T cell differentiation during viral infection. PLoS One 7:e37991
Case, Laure K; Toussaint, Leon; Moussawi, Mohamad et al. (2012) Chromosome y regulates survival following murine coxsackievirus b3 infection. G3 (Bethesda) 2:115-21
Vivier, Eric; Ugolini, Sophie; Blaise, Didier et al. (2012) Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 12:239-52
Tessmer, Marlowe S; Reilly, Emma C; Brossay, Laurent (2011) Salivary gland NK cells are phenotypically and functionally unique. PLoS Pathog 7:e1001254
Reilly, Emma C; Wands, Jack R; Brossay, Laurent (2010) Cytokine dependent and independent iNKT cell activation. Cytokine 51:227-31

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