Innate Regulation of CD8+ T cells during West Nile virus Neuroinvasive Disease Public

Abstract

Neuroinvasive West Nile virus (WNV) infection requires CD8⁺ T cell responses for virologic control in the central nervous system (CNS). Here, we investigate the regulation of CD8+ T cells in the CNS- draining lymph nodes (LNs), meninges, and brain parenchyma in a mouse model of WNV infection. First, we characterized WNV pathogenesis and the WNV-specific CD8+ T cell response in these various anatomic compartments. We found that the meninges and CNS-draining LNs have detectable WNV RNA early during pathogenesis. WNV-specific CD8⁺ T cells from the periphery and CNS-draining lymph nodes exhibited similar profiles , whereas WNV-specific CD8⁺ T cells from meninges and brain had distinct cytokine secretion, expression of activation markers, and functionality. Thus, CNS localized WNV-specific CD8+ T cells are subject to unique regulation during WNV infection. To explore how CNS-specific regulation occurs, we next investigated cell-intrinsic regulators of CD8+ T cell function in the CNS. Mitochondrial antiviral signaling (MAVS) protein, the central adaptor protein for RIG-I like receptor (RLR) signaling, is essential for promoting immunity against WNV infection in the CNS. MAVS is expressed in nearly every cell and is localized on the mitochondria. Here, we find that MAVS is found within CD8+ T cells and functions in a cell-intrinsic manner to promote mitochondrial respiration and cell proliferation. We demonstrate that ablation of MAVS in antigen-specific CD8+ T cells leads to dysregulated oxidative phosphorylation transcriptional profiles and decreased mitochondrial potential in vivo during virus infection. Through adoptive transfer experiments, we determine that MAVS is required for expansion of antigen-specific CD8+ T cells. Mechanistically, we found that MAVS functions in CD8+ T cells by positively regulating cell proliferation during virus infection. Our findings identify a non-canonical role for MAVS as a positive regulator of mitochondrial respiration and cell proliferation of antigen-specific CD8+ T cells during WNV neuroinvasive disease. 

Table of Contents

Introduction (1-22)

-         WNV pathogenesis and Immunity (1-9)

-         CD8+ T cells during neuroinvasive WNV disease (9-14)

-         Innate immune signaling during viral infection (14-19)

-         Summary (20)

-         Figure 1. CD8+ T cells use cytolytic and noncytolytic mechanisms to control virus in the CNS (21)

-         Figure 2. MAVS is the central hub for the Rig-I like receptor signaling pathway (22)

Part 1: Entry of West Nile virus into the central nervous system draining lymphatics precedes differential programming of CD8+ T cells in the brain (23-59)

-         1.1: Introduction (25- 28)

-         1.2: Results (29- 38)

-         1.3: Discussion (39- 44)

-         1.4: Materials and methods (45- 49)

-         1.5: Figure legends (50-53)

-         1.6: Figure Set (55-59)

o  Figure 1: WNV seeds the CNS-draining lymph nodes and meninges prior to parenchymal invasion (55)

o  Figure 2: Activated dendritic cell kinetics differ between the CNS-draining lymph nodes, meninges, and parenchyma (56)

o  Figure 3: Localization to the meninges, brain, and CNS-draining lymph nodes changes WNV-specific CD8+ T cell activation (57)

o  Figure 4: CNS-localized W4B cells are transcriptionally distinct from splenic cells (58)

o  Figure 5: W4B cells from the CNS have polyfunctional cytokine secretion and efficiently control WNV (59)

Part 2: Cell-intrinsic MAVS regulates mitochondrial metabolism to promote CD8+ T cell proliferation. (60- 104)

-         2.1: Introduction (62- 64)

-         2.2: Results (65- 74)

-         2.3: Discussion (74- 77)

-         2.4: Materials and methods (77-82)

-         2.5: Figures (85- 96)

o  Figure 1: MAVS regulates mitochondrial number and elongation in activated CD8+ T cells (85-86)

o  Figure 2: MAVS promotes oxidative phosphorylation in activated CD8+ T cells (87-88)

o  Figure 3: MAVS-mediated metabolism promotes CD8+ T cell proliferation (89-90)

o  Figure 4: Mavs^-/- W4B cells have dysregulated metabolic profiles during WNV infection (91-92)

o  Figure 5: Cell-intrinsic MAVS promotes antigen-specific CD8+ T cell accumulation and cytotoxicity during WNV infection (93-93)

o  Figure 6: MAVS promotes proliferation of antigen-specific CD8+ T cells during viral infection (95-96)

-         2.6: Supplemental Figures (97-104)

Discussion (105- 115)

-         CD8+ T cell programming differs based on anatomic location (105- 109)

-         MAVS and the mitochondrion (109-112)

-         T cells and CNS function (112- 115)

References (116-135)

 

 

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Virology Health Sciences, Immunology
Mot-clé	CD8+ T cell West Nile virus
Committee Chair / Thesis Advisor	Mehul Suthar, Emory University
Committee Members	Haydn Kissick, Emory University Jeremy Boss, Emory University Jacob Kohlmeier, Emory University Arash Grakoui, Emory University

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