Vaccination is a cost-effective means of promoting public health. It depends on the ability of the adaptive immune system, comprising T and B lymphocytes, to mount a rapid protective response to a second infection. Cytotoxic T lymphocytes which express the CD8 marker, are of vital importance in the response to many intracellular infectious agents. Our goal is to shed light on the factors that are involved in generating an effective CD8+ T cell response to pathogen and in promoting the differentiation of the primary effector cells into long-lived memory. It has recently become clear that helper T lymphocytes which express the CD4 marker, are critically involved in achieving this desired goal. Even in the face of infection with a virulent pathogenic virus or intracellular bacterium, the CD8 response requires the response of CD4+ T cells. This contribution may be via the activation of antigen presenting cells or via secretion of cytokines, such as IL-2, which may signal directly to the CD8+ T cells. CD4+ T cells are also required for the long term health and maintenance of CD8 memory cells once they are formed. Using infectious agents such as lymphocytic choriomeningitis virus and Listeria monocytogenes to infect mice we will probe the contribution of CD4+ T cells during the priming or vaccination stage and during memory maintenance.
Specific Aim 1. To investigate the role of CD4+ T cells in maintaining the numbers, health and function of CD8+ memory T cells after the primary response is over. This entails asking which subset of CD4+ T cells provides the maintenance function, and its underlying basis. We have developed the helper-deficient, HD-/- mouse bearing a point mutation in the transcription factor Th-POK, as an ideal model in which to address these questions.
Specific Aim 2. To investigate the factors, such as IL-2 signaling, that are relevant in programming the complete differentiation of pathogen-specific CD8+ T cells into memory cells capable of mounting a robust secondary response to pathogen rechallenge. The goal of vaccination is to generate a pool of memory lymphocytes specific for a pathogen which can protect us for a lifetime. Subsets of T lymphocytes, helpers and killers, must cooperate to achieve protection against many viral and bacterial infections. Our research will shed light on this cooperation for the promotion of long-lived protective immunity. Vaccination against infectious disease is the most cost-effective strategy in promoting human health. Our research is aimed at discovering the conditions that make long-term protection possible following vaccine delivery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019335-32
Application #
8204846
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Ferguson, Stacy E
Project Start
1990-06-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
32
Fiscal Year
2012
Total Cost
$415,116
Indirect Cost
$149,016
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Mehlhop-Williams, Erin R; Bevan, Michael J (2014) Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. J Exp Med 211:345-56
Park, Heon; Tsang, Mark; Iritani, Brian M et al. (2014) Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proc Natl Acad Sci U S A 111:7066-71
Chu, Talyn; Tyznik, Aaron J; Roepke, Sarah et al. (2013) Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner. Cell Rep 3:701-8
Zhang, Nu; Bevan, Michael J (2013) Transforming growth factor-* signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39:687-96
Prlic, Martin; Bevan, Michael J (2011) Cutting edge: *-catenin is dispensable for T cell effector differentiation, memory formation, and recall responses. J Immunol 187:1542-6
Pipkin, Matthew E; Sacks, Jilian A; Cruz-Guilloty, Fernando et al. (2010) Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32:79-90
Zehn, Dietmar; Turner, Michael J; Lefrancois, Leo et al. (2010) Lack of original antigenic sin in recall CD8(+) T cell responses. J Immunol 184:6320-6
Wakim, Linda M; Woodward-Davis, Amanda; Bevan, Michael J (2010) Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc Natl Acad Sci U S A 107:17872-9
Bevan, Michael J (2010) The earliest knockouts. J Immunol 184:4585-6
Setoguchi, Ruka; Taniuchi, Ichiro; Bevan, Michael J (2009) ThPOK derepression is required for robust CD8 T cell responses to viral infection. J Immunol 183:4467-74

Showing the most recent 10 out of 83 publications