During chronic infections such as those caused by HIV-1, hepatitis C virus (HCV), and lymphocytic choriomeningitis virus (LCMV), as well as during tumor outgrowth, antigen-specific CD8 T cells often progressively lose function in a step-wise manner. Understanding the factors that impact CD8 T cell responses during chronic viral infections is necessary for the design of effective immunotherapeutic strategies. Recent reports demonstrate that a discrete subset of exhausted CD8 T cells exists that displays stem cell-like properties, including the ability to self-renew and further differentiate in vivo. Importantly, this subset of cells is exquisitely responsive to anti-PD-L1 immunotherapy during chronic LCMV clone 13 infection. Hence, determining the mechanisms that promote the maintenance and survival of stem-like CD8 T cells during chronic viral infection is of central importance. We present preliminary findings that show a distinct fraction of the virus-specific stem-like CD8 T cells express cell surface N-glycans with ?-2,6 linked sialic acids, a posttranslational modification mediated by the glycosyltransferase ST6Gal-I. Importantly, published studies, as well as our own data, establish that this enzyme is associated with pluripotency and stemness. Together, these data lead us to hypothesize that ST6Gal-I sialylation positively regulates CD8 T cell stemness and responsiveness to immunotherapy during chronic viral infection. Our objectives of this exploratory R21 application are to:
Aim 1. Determine if ST6Gal-I sialylation identifies stem-like CD8 T cells during chronic viral infection.
Aim 2 : Determine how modulation of ST6Gal-I sialylation impacts CD8 T cell stemness. Collectively, these studies are designed to provide new information regarding the impact of cell surface sialylation of CD8 T cell responses, including CD8 T cell stemness and exhaustion.

Public Health Relevance

Chronic viral infections are associated with the emergence of exhausted CD8 T cells and targeted interventions aimed at reinvigorating these dysfunctional responses show promise in respect to viral control. By investigating how specific factors modulate the responsiveness of virus-specific CD8 T cells to prolonged viral infection, as well as immunotherapy, we will gain valuable new information to shape the development of new anti-viral strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI142641-02
Application #
9820238
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Jiang, Chao
Project Start
2018-11-07
Project End
2020-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294