To study T cell exhaustion in leukemia, Chen et al. generated a TCR-transgenic mouse specific for a currently unknown leukemia antigen (TCRTg101). Adoptively transferred TCRTg101 cells did not extend survival of leukemia-bearing mice, suggesting dysfunction. As TCRTg101 cells proliferated, they acquired molecular and transcriptional features of exhaustion (PD-1, LAG-3, Tox) and lost functionality (cytokine secretion and lytic ability). This phenotype, mediated through direct antigen presentation by leukemia cells, was largely irreversible; proliferated TCRTg101 cells from diseased hosts did not expand in a secondary host or respond to anti-PD-1/LAG-3.
Contributed by Alex Najibi
ABSTRACT: The existence of a dysfunctional CD8(+) T cell state in cancer is well established. However, the degree to which CD8(+) T cell fates are influenced by the context in which they encounter cognate tumor antigen is less clear. We previously demonstrated that CD8(+) T cells reactive to a model leukemia antigen were deleted by antigen cross-presenting type 1 conventional dendritic cells (cDC1s). Here, through a study of T cell receptor (TCR) transgenic CD8(+) T cells (TCR(Tg101)) reactive to a native C1498 leukemia cell antigen, we uncover a different mode of T cell tolerance in which TCR(Tg101) undergo progressive expansion and differentiation into an exhausted state. Antigen encounter by TCR(Tg101) requires leukemia cell major histocompatibility complex (MHC)-I expression and is independent of DCs, implying that leukemia cells directly mediate the exhausted TCR(Tg101) phenotype. Collectively, our data reveal that leukemia antigens are presented to CD8(+) T cells via discrete pathways, leading to distinct tolerant states.
Author Info: (1) Department of Medicine, University of Chicago, Chicago, IL, USA. (2) Committee on Immunology, University of Chicago, Chicago, IL, USA. (3) Committee on Immunology, University o
Author Info: (1) Department of Medicine, University of Chicago, Chicago, IL, USA. (2) Committee on Immunology, University of Chicago, Chicago, IL, USA. (3) Committee on Immunology, University of Chicago, Chicago, IL, USA. (4) Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA. (5) Department of Medicine, University of Chicago, Chicago, IL, USA; Committee on Immunology, University of Chicago, Chicago, IL, USA; University of Chicago Comprehensive Cancer Center, Chicago, IL, USA. Electronic address: jkline@medicine.bsd.uchicago.edu.
