Delineate common cellular circuits that orchestrate T cell immunity in chronic infections and tumors

• Applicant: Professor Dr. Dietmar Zehn
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 500678236

Reawakening T cell-mediated immunity in cases of failed immunoptorection has been tremendously successful and holds significant promises for treating patients with chronic infection or tumors. Both induce dysfunctional virus-specific CD8 T cells known as T cell exhaustion. Terminally exhausted T cells, characterized by declined proliferative capacity and production of effector molecules and sustained expression of co-inhibitory receptors, are refractory to immune checkpoint blockade. T cell exhaustion constitute a major limiting factor for immunotherapy but it is from an evolutionary perspective a key process which has evolved to restrict immunopathology in chronic infection with sustained virus production. In addition, emerging works reveal that a unique subset of virus-specific CD8+ T cells expressing the transcription factor T-cell factor 1 (TCF1), referred as progenitor exhausted T cells, display a stem-like phenotype and exhibit robust proliferation and differentiation into effector CD8+ T cells. These cells constitute a starting point for immunotherapy induced anti-tumor and anti-viral responses. However, it remains unclear which cellular and molecular factors could orchestrate the formation of stem-like CD8 exhausted T cells into the various subsets that can generate and whether we could more effectively exploit the underlying regulations to augment anti-viral T cell responses. Here, we aim to elucidate the detailed molecular and cellular crosstalk between DCs, including pDCs and conventional type I dendritic cells (cDC1s), and CD8 T cells in chronic infection and further investigate how CD4 T cells can fine-tune this process to guide host anti-viral immunity in chronic viral infection. Knowledge of such specialized crosstalk can serve as a springboard to broaden our horizon on cellular and molecular machineries that guiding CD8 T cell differentiation in chronic antigen exposure contexts.

• DFG Programme: Research Grants
• International Connection: Switzerland
• Cooperation Partner: Professor Ping-Chih Ho, Ph.D.