CD8+ T cells play a critical role in defense against viral, intracellular bacterial, and protozoan infections. To confer protective immunity, vaccines against these agents need to elicit potent CD8+ T-cell memory. Despite recognition of their importance in vaccinations, the underlying mechanisms in the generation of memory T cells remains poorly understood. The magnitude of T cell memory is dependent upon, the extent of clonal expansion and, the subsequent death of activated antigen-specific T cells. Understanding the generation of memory T cells is contingent upon elucidating the mechanisms that regulate proliferation and apoptosis of activated CD8+ T cells in vivo. Our long-term goal is to understand the molecular and cellular basis of CD8+ T cell memory. We have initiated studies investigating the role of TNF receptors (TNFRs) in regulating the generation of CD8+ memory T cells using the lymphocytic choriomeningitis virus (LCMV) model in mice. Preliminary studies have revealed that there is a dramatic enhancement in the number of LCMV-specific memory CD8+ T cells in TNFR I-and TNFR I & II-deficient mice, as compared to wild type (+1+) mice. The goal of this application is to understand the mechanisms by which TNFRs regulate generation of memory CD8+ T cells. We hypothesize that lack of apoptotic signals in TNFR-deficient mice leads to increased number of memory CD8+ T cells, that otherwise would be slated for deletion. The objectives of this proposal are three fold: First, to elucidate the mechanistic basis of downregulating CD8+ T cell responses by TNFRs, by (1) examining the effect of TNFR deficiency on the proliferation and apoptosis of LCMV-specific CD8+ T cells in vitro and in vivo; (2) determining the ligand responsible for TNFR-mediated effects:TNFa vs. LTa. Second, to dissect the importance of TNFR signaling on CD8+ T cells (direct effects) vs. non-CD8+ T cells (indirect effects) in regulating the generation of LCMV-specific memory CD8+ T cells, by using bone marrow chimeras and CD4-deficient mice. Third, to examine the role of TNFRs on the functional attributes of LCMV specific CD8+ T cells in vitro and in vivo. Immunological memory can be accounted for by both quantitative (increased number of antigen-specific T cells) and qualitative (heightened sensitivity) differences in memory T cells. Our preliminary studies show that loss of TNFR I lead to increased number (""""""""quantity"""""""") of memory CD8+ T cells. We will examine for qualitative differences between TNFR-deficient and +/+ LCMV-specific memory CD8+ T cells by comparing the activation thresholds to produce cytokines and perform cell-mediated cytotoxicity as a function of antigen concentration, CD8 requirement, and time. The function of TNFR deficient memory CD8+ T cells will be tested in vivo in (1) LCMV-immune mice and (2) DNA vaccine-immunized mice by studying protective immunity against lethal CD8+ T cell-mediated CNS immunopathology. Despite several lines of evidence of a suppressive role for TNF in T-cell-mediated autoimmunity, the underlying regulatory mechanisms are not well understood. The proposed experiments in this application will provide critical information towards (i) development of effective vaccines; (ii) understanding the pathogenesis of autoimmune disorders, and (iii) formulating immunotherapies against immune-mediated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048785-05
Application #
7025677
Study Section
Special Emphasis Panel (ZRG1-SSS-F (01))
Program Officer
Miller, Lara R
Project Start
2002-03-01
Project End
2008-01-31
Budget Start
2006-03-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$284,162
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Contreras, Amanda; Beems, Megan V; Tatar, Andrew J et al. (2018) Co-transfer of tumor-specific effector and memory CD8+ T cells enhances the efficacy of adoptive melanoma immunotherapy in a mouse model. J Immunother Cancer 6:41
Kim, Eui Ho; Neldner, Brandon; Gui, Jingang et al. (2016) Mcl-1 regulates effector and memory CD8 T-cell differentiation during acute viral infection. Virology 490:75-82
Contreras, Amanda; Sen, Siddhartha; Tatar, Andrew J et al. (2016) Enhanced local and systemic anti-melanoma CD8+ T cell responses after memory T cell-based adoptive immunotherapy in mice. Cancer Immunol Immunother 65:601-11
Mahvi, David A; Meyers, Justin V; Tatar, Andrew J et al. (2015) Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice. J Immunother 38:54-61
Gasper, David J; Tejera, Melba Marie; Suresh, M (2014) CD4 T-cell memory generation and maintenance. Crit Rev Immunol 34:121-46
Kim, Eui Ho; Gasper, David J; Lee, Song Hee et al. (2014) Bach2 regulates homeostasis of Foxp3+ regulatory T cells and protects against fatal lung disease in mice. J Immunol 192:985-95
Wentworth, Lucy; Meyers, Justin V; Alam, Sheeba et al. (2013) Memory T cells are uniquely resistant to melanoma-induced suppression. Cancer Immunol Immunother 62:149-59
Jatzek, Anna; Marie Tejera, Melba; Plisch, Erin H et al. (2013) T-cell intrinsic and extrinsic mechanisms of p27Kip1 in the regulation of CD8 T-cell memory. Immunol Cell Biol 91:120-9
Tejera, Melba Marie; Kim, Eui Ho; Sullivan, Jeremy A et al. (2013) FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory. J Immunol 191:187-99
Kim, Eui Ho; Sullivan, Jeremy A; Plisch, Erin H et al. (2012) Signal integration by Akt regulates CD8 T cell effector and memory differentiation. J Immunol 188:4305-14

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