Vaccine strategies to achieve effective immunity to pathogens must establish short-lived effector and a reserve of long-lived memory T cells. Mycobacterium tuberculosis and Schistosoma mansoni represent epidemic pathogens for which vaccine development has been difficult to achieve. These pathogens evoke T helper (Th) cell-mediated, mononuclear cell-rich, sequestration responses known as granulomas (GR). The role of CD4+ Th cells in the GR response to these pathogens is well established. Moreover, mycobacterial and schistosomal antigens, respectively elicit polarized Th1 (type-1) and Th2 (type-2) hypersensitivity-type GR formation. We have examined the role of chemoattractant proteins in these responses with the objective to identify critical chemokines and chemokine receptors required for effective and appropriate responses to these pathogens. We identified CC-chemokine receptor 4 (CCR4) as a T and dendritic cell-expressed chemokine receptor that participates in the GR response, with particular relevance to the mycobacterial response. Initial analyses suggested that CCR4 mediates interactions with antigen presenting dendritic cells (DCs) to promote survival or maturation of Th effector/memory cells. The studies proposed herein will test the hypothesis that pathogen- elicited CD4+ Th1 and Th2 cells have different chemokine requirements for sustenance of effector and central memory function. Specifically, CD4+ Th1 effector and central memory responses to mycobacteria require CCR4-mediated interactions with antigen presenting myeloid dendritic cells (mDCs). In contrast, Th2 effectors may utilize CCR4 for tissue mobilization, but Th2 central memory is sustained through alternative antigen presenting cells. This hypothesis will be tested under conditions of Mycobacterium bovis and Schistosoma mansoni exposure by way of the following aims.
Aim 1 will define the role of CCR4 in the induction of innate, adaptive and regulatory effectors.
Aim 2 will determine the contribution of T cell CCR4 expression to the generation and mobilization of short-lived effector memory CD4+ Th cells.
Aim 3 will assess the contribution of T cell CCR4 expression to the maintenance and elicitation of central memory CD4+ Th cells.
Aim 4 will determine the contribution of myeloid dendritic cell (mDC) CCR4 expression to the generation and sustenance of effector and central memory CD4+ Th responses.
Aim 5 will determine the contribution of CCR4 to mDC maturation, function and localization. Methodologies will include the use of CCR4 targeted knockout mice, recombinant ovalbumin-producing M. bovis BCG-strain (BCG-OVA), adoptive D10.11 transgenic T cell transfer, preparation of bone marrow chimeras, mDC preparation and culture, gene expression analysis, and flow cytometry. Mycobacterial and helminth infections are responsible for a profound degree of global morbidity and mortality. The studies proposed will aid the design of improved approaches to vaccine development and therapies to control chronic destructive inflammatory responses.

Public Health Relevance

Mycobacterial and helminthic parasite infections are responsible for a profound degree of global morbidity and mortality. This project represents an extension of a broad systematic analysis of cellular attractant proteins, called chemokines, in immuno-inflammatory responses evoked by mycobacterial and helminth pathogens. The proposed studies will reveal the participation of key molecular mediators in order to design improved approaches to vaccine development and therapies to control chronic destructive inflammatory responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043460-12
Application #
8299159
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Minnicozzi, Michael
Project Start
1998-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
12
Fiscal Year
2012
Total Cost
$246,985
Indirect Cost
$50,965
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Chensue, Stephen W (2013) Chemokines in innate and adaptive granuloma formation. Front Immunol 4:43
Chiu, Bo-Chin; Martin, Brian E; Stolberg, Valerie R et al. (2013) Cutting edge: Central memory CD8 T cells in aged mice are virtual memory cells. J Immunol 191:5793-6
Chiu, Bo-Chin; Martin, Brian E; Stolberg, Valerie R et al. (2013) The host environment is responsible for aging-related functional NK cell deficiency. J Immunol 191:4688-98
Stolberg, Valerie R; Chiu, Bo-chin; Martin, Brian E et al. (2011) Cysteine-cysteinyl chemokine receptor 6 mediates invariant natural killer T cell airway recruitment and innate stage resistance during mycobacterial infection. J Innate Immun 3:99-108
Stolberg, Valerie R; Chiu, Bo-Chin; Schmidt, Brian M et al. (2011) CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection. Am J Pathol 178:233-44
Hu, Jerry S; Freeman, Christine M; Stolberg, Valerie R et al. (2006) AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation. Am J Pathol 169:424-32
Freeman, Christine M; Stolberg, Valerie R; Chiu, Bo-Chin et al. (2006) CCR4 participation in Th type 1 (mycobacterial) and Th type 2 (schistosomal) anamnestic pulmonary granulomatous responses. J Immunol 177:4149-58
Freeman, Christine M; Chiu, Bo-Chin; Stolberg, Valerie R et al. (2005) CCR8 is expressed by antigen-elicited, IL-10-producing CD4+CD25+ T cells, which regulate Th2-mediated granuloma formation in mice. J Immunol 174:1962-70
Chiu, Bo-Chin; Freeman, Christine M; Stolberg, Valerie R et al. (2004) Impaired lung dendritic cell activation in CCR2 knockout mice. Am J Pathol 165:1199-209
Chiu, Bo-Chin; Freeman, Christine M; Stolberg, Valerie R et al. (2004) The innate pulmonary granuloma: characterization and demonstration of dendritic cell recruitment and function. Am J Pathol 164:1021-30

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