Cytotoxic CD4 Th1 cells are emerging as a physiologically relevant and therapeutically useful T cell lineage that can successfully target tumors. Until now the cellular and molecular pathways that program their differentiation have been poorly understood. Our preliminary data demonstrates that CD134 (OX40) costimulation induces na?ve self-reactive CD4 T cells to differentiate into cytotoxic Th1 effectors, and the addition of CD137 (4-1BB) costimulation maximizes their clonal expansion. This differentiation process requires IL-2, and the T-box transcription factor Eomesodermin (Eomes). The experimental plan will test if Eomes programs bone fide memory potential. If so, this will help to resolve the recurring controversy regarding the existence and basis of CD4 T cell memory. Perhaps our most unexpected observation is that CD134 plus CD137 dual costimulation-programmed antigen-specific cytotoxic CD4 Th1 cells "imprint" antigen - inexperienced bystanding T cells with similar functional capacities. We will test if these polyclonal bystander - activated effectors can be exploited to target antigen-loss variant tumor cells that have down-regulated epitopes recognized by specific cytotoxic T cells elicited by immunotherapy, and if these bystander T cells mediate pathogenic side effects associated with immunotherapy. In summary, the proposed experiments will mechanistically dissect how CD134 plus CD137 dual costimulation induces specific and bystander cytotoxic CD4 Th1 cells, and develop therapeutic strategies to harness their potential to control tumor growth that can be translated clinically to treat human cancer patients.

Public Health Relevance

Cytotoxic CD4 Th1 cells are emerging as a therapeutically useful T cell lineage that can target tumors, but up till now the pathways that program their differentiation have been poorly understood. Our preliminary findings reveal that the CD134 (OX40) plus CD137 (4-1BB) costimulatory pathways induce cytotoxic CD4 Th1 cell differentiation, and the proposed work will study the underlying mechanisms as well as develop clinically translatable strategies for using dual costimulation to eradicate tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI094640-03
Application #
8604672
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Lapham, Cheryl K
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$341,484
Indirect Cost
$116,484
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
St Rose, Marie-Clare; Taylor, Roslyn A; Bandyopadhyay, Suman et al. (2013) CD134/CD137 dual costimulation-elicited IFN-? maximizes effector T-cell function but limits Treg expansion. Immunol Cell Biol 91:173-83