The CD4+ T cell response to CNS viral infection

Bibliographic Details
Main Author:	Lin, Adora A.
Language:	English
Published:	University of Cincinnati / OhioLINK 2009
Subjects:	Immunology T cells LCMV androgens NKT cells IFN-g macrophages
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1235330516

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin12353305162021-08-03T06:13:08Z The CD4+ T cell response to CNS viral infection Lin, Adora A. Immunology T cells LCMV androgens NKT cells IFN-g macrophages <p>T cell-mediated pathology is a major cause of disease in both infection and autoimmunity. While T cell responses provide protection from pathogens, uncontrolled responses can lead to rampant autoimmunity and immunopathology. In this dissertation, we employed a mouse model of central nervous system (CNS) viral infection to further understand the role and regulation of CD4+ T cell responses in immunopathology. In this model, intracranial (i.c.) infection of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) results in fatal meningitis mediated by CD8+ T cells by day 8 post-infection. I.c. LCMV infection of mice deficient in CD8+ T cells, either by deficiency in β<sub>2</sub> microglobulin (β<sub>2</sub>m<sup>-/-</sup>) or in vivo depletion, results in less severe meningitis and lower mortality rate. CD8+ T cell-deficient mice also develop severe anorexia and weight loss; these symptoms, as well as meningitis, are mediated by anti-viral CD4+ T cell responses and are not affected by viral titer. Thus, this mouse model allows us to directly examine: (i) factors that influence immunopathologic CD4+ T cell responses to viral infection; and (ii) mechanism(s) downstream of CD4+ T cell responses that control immunopathologic disease. Identification of mechanism(s) that control the magnitude and downstream sequelae of the viral-specific CD4+ T cell response will enhance our understanding of the regulation of and our ability to treat immunopathologic disease.</p><p>This dissertation investigated three main hypotheses: (i) androgens and NKT cells independently regulate the quantity and quality of viral-specific CD4+ T cell responses; (ii) type I interferon signaling controls the activation of NKT cells during viral infection; and (iii) type II interferon (IFN-γ) signaling controls recruitment and activation of antigen-presenting cells (APCs) but not viral-specific CD4+ T cell responses. Our work shows that CD4+ T cell production of IFN-γ can regulate immunopathologic disease via signaling to macrophage-lineage cells. Further, such IFN-γ signaling controls chemokine production and antigen-presenting cell (APC) activation within and recruitment to the CNS. However, IFN-γ does not control the magnitude of viral-specific CD4+ T cell responses. Instead, we found that the actions of sex hormones and the action of NKT cells independently regulate the magnitude of viral-specific CD4+ T cell responses. Finally, we found that NKT cells required type I interferon signaling for activation and likely control viral-specific CD4+ T cell responses through their effects on dendritic cell co-stimulatory molecule expression. These findings have significant implications for our understanding of sex differences in susceptibility to autoimmunity and the development of therapies for disease-associated anorexia and neuroinflammatory and immune-mediated diseases.</p> 2009-04-17 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1235330516 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1235330516 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Immunology T cells LCMV androgens NKT cells IFN-g macrophages
spellingShingle	Immunology T cells LCMV androgens NKT cells IFN-g macrophages Lin, Adora A. The CD4+ T cell response to CNS viral infection
author	Lin, Adora A.
author_facet	Lin, Adora A.
author_sort	Lin, Adora A.
title	The CD4+ T cell response to CNS viral infection
title_short	The CD4+ T cell response to CNS viral infection
title_full	The CD4+ T cell response to CNS viral infection
title_fullStr	The CD4+ T cell response to CNS viral infection
title_full_unstemmed	The CD4+ T cell response to CNS viral infection
title_sort	cd4+ t cell response to cns viral infection
publisher	University of Cincinnati / OhioLINK
publishDate	2009
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1235330516
work_keys_str_mv	AT linadoraa thecd4tcellresponsetocnsviralinfection AT linadoraa cd4tcellresponsetocnsviralinfection
_version_	1719432921811517440

The CD4+ T cell response to CNS viral infection

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