ORCID
http://orcid.org/0000-0003-3216-5574
Date of Award
Spring 5-15-2020
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The adaptive immune response consists of interplay between CD4 T cells, CD8 T cells, and B cells which function in control of pathogen in the host. T cells responding via their TCR express cytokines and costimulatory molecules that support direct effector activity and also promote high-affinity antibody generation through augmenting of B cell responses. However, the molecular components that contribute T cell function to balance viral control and the potential for host damage are incompletely understood. In this work, we establish a role for the adaptor molecule CD2AP in modulation of CD4 T cell responses to chronic LCMV infection in mice though the generation of T Follicular Helper cells. We find that CD2AP modulates TCR signaling during viral infection and its deletion augments the germinal center response and generation of neutralizing antibodies. CD8 T cells are subject to negative regulation via inhibitory receptors such as PD-1 which is correlated with T cell “exhaustion”. Here we determine the functions of PD-1 during different stages of chronic viral infection which reveals an important role in maintenance of durable immunity. Treating mice infected by a chronic strain of LCMV with PD-1 blockade at the peak of viremia does not cause fatal immunopathology, but eventually resulted in disruption of lymphoid architecture and a reduction in the CD8 T cell response. Furthermore, transient blockade of type-I interferon completely prevented death of LCMV-infected mice treated with PD-1 blockade at the time of infection, intriguingly a combination of the transient blocking IFNAR signaling and delayed PD-1 blockade, which alone would compromise antiviral immunity, accelerated viral clearance without causing immunopathology. These results indicate that harnessing CD8 T cells at early stages of chronic viral infection in paradoxically benefits long-term immunity and eventually results in enhanced control of viral infection.
Language
English (en)
Chair and Committee
Andrey S. Shaw
Committee Members
Paul M. Allen, Chyi-Song Hsieh, Kenneth M. Murphy,
Recommended Citation
Raju, Saravanan, "Signaling Mechanisms in Adaptive Immunity" (2020). Arts & Sciences Electronic Theses and Dissertations. 2234.
https://openscholarship.wustl.edu/art_sci_etds/2234
Included in
Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons