Viruses have co-evolved with their hosts for centuries and as a result have developed mechanisms of immune escape. The simplest mechanism is mutation of surface epitopes recognized by antibodies. However, hosts have countered with cytotoxic CD8 T cells that can recognize mutated viruses via conserved, internal proteins. These CD8 T cell epitopes are less susceptible to immune pressure as they are essential for viral fitness. Importantly, once activated, a portion of the anti-viral T cells will persist long-term, some within non-lymphoid tissues as tissue-resident memory cells (TRM) poised to respond rapidly after subsequent infections. Unfortunately, however, not all TRM are created equal. TRM derived from respiratory infection are not stable, and as their numbers diminish, cross-protection against related viruses is also lost. Thus, understanding the mechanisms which prevent the development of durable TRM is essential for designing interventions to extend their protective capacity. The goal of this application is to determine how the early T cell programmatic events unique to viral infections of the lung and the ensuing respiratory immune response promote a developmental divergence from the archetypical memory program associated with long-lived memory. In preliminary data, we identified a population of transitional CCR2+ monocyte/dendritic cell (moDC) which emigrate to the lung draining lymph node coordinate with T cell activation and only after respiratory infection. These moDC develop in response to type I IFN signaling and express high levels of the inhibitory molecule PD-L1. Importantly, selective depletion of moDC early after infection modifies the phenotype of the resultant TRM to resemble conventional, long-lived TRM, suggesting that these moDC suppress the conventional TRM program. Here, we will extend our preliminary studies to define the pathogen-driven signals which elicit the development and recruitment of these suppressive cells to the site of priming. Additional studies will define mechanistically how moDC interface with anti-viral CD8 T cells in the lymph node and whether release of the moDC suppression prolongs TRM survival in the lung and concomitantly extends heterologous protection. Together, these studies will provide a clear picture of the complex relationship between virus and host where specific pathogen-driven immune responses in place to temper local immunity may also divert the responding CD8 T cells towards a short-lived respiratory TRM fate. Translation of this knowledge will improve vaccines against respiratory viruses which remain a public health concern.

Public Health Relevance

CD8 T lymphocytes activated after respiratory infection are capable of recognizing viral variants and mediating protection after heterologous infection; however, these cells are programmed with a limited lifespan. The goal of this project is to determine how properties of the virus and certain environmental barriers specific to the lung favor the development of these short-lived T cells. A better understanding of how anti-viral immunity is inherently regulated in the lung is important for extending the lifespan of cross-protective memory CD8 T cells and ultimately improving vaccines against common respiratory infections which remain a public health concern.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI131093-01
Application #
9299765
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Kelly, Halonna R
Project Start
2017-01-12
Project End
2018-12-31
Budget Start
2017-01-12
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$225,000
Indirect Cost
$75,000
Name
University of Georgia
Department
Biology
Type
Other Domestic Higher Education
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Shane, Hillary L; Reagin, Katie L; Klonowski, Kimberly D (2018) The Respiratory Environment Diverts the Development of Antiviral Memory CD8 T Cells. J Immunol 200:3752-3761
Reagin, Katie L; Klonowski, Kimberly D (2018) Incomplete Memories: The Natural Suppression of Tissue-Resident Memory CD8 T Cells in the Lung. Front Immunol 9:17