CDS T cell responses are remarkably diverse and play vital roles in immune mediated viral control. Thus, there is a crucial need to decipher the developmental cues that drive the differentiation of phenotypically and functionally distinct CDS T cell subsets, define how these constituents cooperate to achieve infection control, and delineate the signals that help sustain these populations over time. Our proposal is based upon a series of recently published and preliminary findings that have advanced our understanding of the importance of intercellular adhesion molecule (ICAM)-I in determining the composition and properties of anti-viral CDS T cell responses. The experimental plan is designed to capitalize on these observations and generate novel fundamental insights into how and when ICAM-1 interactions configure the memory CDS T cell pool, and program protective efficacy. In addition, we will also determine whether tactically targeting ICAM-1 interactions improves immunity and viral control. Promisingly, we have shown that mitigating ICAM-1 interactions preserves anti-viral CDS T cells which usually succumb to exhaustion during chronic viral infections. Thus, our studies have the potential to impact the field by providing new fundamental information regarding how CDS T cell responses are regulated, as well as deliver proof of principle evidence that blocking ICAM-1 interactions is a viable strategy for augmenting immunity to acute, chronic, and bystander infections. This is especially significant as practical strategies to enhance responses by manipulating the anti-viral CDS T cell pool are limited. We also propose to integrate our ICAM-1 studies, showing the retention of effector-phenotype CDS T cells following infection, with our new discovery that IL-21 helps to maintain effector-memory CDS T cells. Given the ubiquitous roles of CDS T cells in anti-viral defense our studies may broadly impact the field by defining the principles that govern and configure the development of these responses. Significantly, they will decipher how ICAM-1 interactions skew the composition of the antiviral CDS T cell pool and whether this can be targeted to enhance immunity.

Public Health Relevance

There is a critical need to develop better strategies to promote viral control and limit pathogenesis, that are ideally directed by an in-depth fundamental understanding of disease processes and host protection mechanisms. This project is designed to provide novel insights into the roles of adhesion molecules in antiviral defence that may broadly impact the field by identifying potential new therapeutic targets to improve immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109962-01
Application #
8677087
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$303,455
Indirect Cost
$66,269
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Nguyen, Trang T T; Graf, Beth A; Randall, Troy D et al. (2017) sIgM-Fc?R Interactions Regulate Early B Cell Activation and Plasma Cell Development after Influenza Virus Infection. J Immunol 199:1635-1646
Savage, Hannah P; Yenson, Vanessa M; Sawhney, Sanjam S et al. (2017) Blimp-1-dependent and -independent natural antibody production by B-1 and B-1-derived plasma cells. J Exp Med 214:2777-2794
Nguyen, Trang T T; Kläsener, Kathrin; Zürn, Christa et al. (2017) The IgM receptor Fc?R limits tonic BCR signaling by regulating expression of the IgM BCR. Nat Immunol 18:321-333
Meza-Perez, Selene; Randall, Troy D (2017) Immunological Functions of the Omentum. Trends Immunol 38:526-536
Botta, Davide; Fuller, Michael J; Marquez-Lago, Tatiana T et al. (2017) Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection. Nat Immunol 18:1249-1260
Baumgarth, Nicole (2017) A Hard(y) Look at B-1 Cell Development and Function. J Immunol 199:3387-3394
Nellore, Anoma; Randall, Troy D (2016) Narcolepsy and influenza vaccination-the inappropriate awakening of immunity. Ann Transl Med 4:S29
Tian, Yuan; Cox, Maureen A; Kahan, Shannon M et al. (2016) A Context-Dependent Role for IL-21 in Modulating the Differentiation, Distribution, and Abundance of Effector and Memory CD8 T Cell Subsets. J Immunol 196:2153-66
Nguyen, Trang T T; Baumgarth, Nicole (2016) Natural IgM and the Development of B Cell-Mediated Autoimmune Diseases. Crit Rev Immunol 36:163-177
Tian, Yuan; Mollo, Sarah B; Harrington, Laurie E et al. (2016) IL-10 Regulates Memory T Cell Development and the Balance between Th1 and Follicular Th Cell Responses during an Acute Viral Infection. J Immunol 197:1308-21

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