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Abstract

Grant Number:	5P01AI061298-020002
Project Title:	Antifungal Memory Immunity

PI Information:	Name	Email	Title
	KLEIN, BRUCE S.	bsklein@wisc.edu	PROFESSOR

Abstract: CD4 T-cells are thought to be a key player in protective immunity to blastomycosis and histoplasmosis, two of the principal systemic mycoses of humans and animals. However, we have recently shown, that CD8 T-cells alone, without CD4 T-cell help, can mediate efficient vaccine-induced immunity to these fungi. Resistance by CD8 T-cells was restricted by MHC class I and required the production of IFN-gamma, TNF-alpha and GM-CSF. Here, we propose to analyze the mechanisms by which these vaccines trigger and maintain long-term CD8 T cell responses to protect against experimental pulmonary blastomycosis and histoplasmosis. We will study the components of the tripartite interaction between antigen presenting cell, T-cell and antigen peptide to define the cellular and molecular requirements for priming, activation and maintenance of protective CD8 T-cells responses using in vivo and in vitro models. We postulate that memory CD8 T ceils are initiated and maintained independent of CD40/CD40L signaling, but depend on BT/CD28 co-stimulation and B-cells for survival. We also postulate that without CD4 ligation of CD40 on antigen-presenting cells yeast surface moieties induce dendritic cell (DC) maturation via Toll-like receptors (TLR); DC cross-prime naive CD8 T-cells via exogenous antigens that gain access to class I MHC unconventionally, independent of the transporter associated with antigen processing (TAP). Our aims are: 1) Elucidate factors responsible for initiation and maintenance of CD4-independent CD8 memory. We will validate that CD4 cells are indeed dispensable for long-term CD8 memory, in contrast to current dogma. We will explore the roles of CD40/CD40L and B7/CD28 signaling, and of B-cells in CD8-cell priming in the absence of CD4 help, and in the maintenance and contraction of the CD8 memory pool. Use of transgenic yeast that display an LCMV gp33 T-cell epitope will allow us to track number and function of memory CD8 cells in a way not previously possible in the fungi. 2) Define mechanisms of exogenous antigen cross-presentation to CD8 cells by DC in CD4-deficient hosts. We will explore whether and how TLR condition DC for cross-presentation of exogenous fungal antigens to induce protective CD8 T cell responses. The intracellular route by which exogenous fungal antigens access MHC class I will be studied, including the roles of TAP, degradation and loading of class I in endosomes and MHC binding on peptide regurgitation. Defining the requirements for induction and maintenance of durable memory CD8 T-cells in the absence of CD4 help, and the mechanisms of cross-presentation of exogenous fungal antigens to class I, will enhance the development of vaccine strategies against dimorphic fungi in immune compromised hosts with defective CD4 T cell immunity.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
antifungal antibody, blastomycosis, cytotoxic T lymphocyte, fungal antigen, fungal vaccine, histoplasmosis, immunity, immunologic memory, vaccine evaluation
CD28 molecule, antigen presenting cell, dendritic cell, immune response, toll like receptor
Blastomyces dermatitidis, Histoplasma, genetically modified animal, laboratory mouse

Institution:	UNIVERSITY OF WISCONSIN MADISON
	21 N. Park Street, Suite 6401
	MADISON, WI 537151218
Fiscal Year:	2005
Department:
Project Start:
Project End:
ICD:	NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
IRG:	ZAI1

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