TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

Abstract

Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during anti-tumor responses. Our data showed that the loss of TCF-1 in CD8 T cells also leads to loss of key stimulatory molecules such as CD28. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet. Using both in vitro and in vivo models, we uncovered how TCF-1 regulates critical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches suggested that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulated several critical aspects of T cell function during CD8 T cell response to cancer. Graphical abstract Summary Figure: TCF-1 is required for persistent function of CD8 T cells but dispensable for anti-tumor response. Here, we have utilized a novel mouse model that lacks TCF-1 specifically on CD8 T cells for an allogeneic transplant model. We uncovered a molecular mechanism of how TCF-1 regulates key signaling pathways at both transcriptomic and protein levels. These key molecules included LCK, LAT, ITK, PLC-γ1, p65, ERK I/II, and JAK/STAT signaling. Next, we showed that the lack of TCF-1 impacted phenotype, proinflammatory cytokine production, chemokine expression, and T cell activation. We provided clinical evidence for how these changes impact GVHD target organs (skin, small intestine, and liver). Finally, we provided evidence that TCF-1 regulates NKG2D expression on mouse naïve and activated CD8 T cells. We have shown that CD8 T cells from TCF-1 cKO mice mediate cytolytic functions via NKG2D.

Defining a TCF1-expressing progenitor allogeneic CD8+ T cell subset in acute graft-versus-host disease

“…In this study, we defined a TCF1 + PD-1 + progenitor population that could foster progeny cells producing effector molecules. Combined with the recent observation that TCF1 expression in CD8 + T cells is essential in the pathogenesis of acute GvHD 46 , this provides promising insight into opportunities for the development of therapeutics for acute GvHD. Eliminating the progenitor population or inhibiting the differentiation of the progenitor subset could be useful in mitigating acute GvHD.…”

“…Consistent with the results in chronic viral infection and cancer 12 – 20 , TCF1 + progenitor CD8 + T cells possessed exclusive proliferative potential, were able to differentiate into TCF1 - progeny CD8 + T cells harboring effector molecules via antigenic stimulation, and predominantly localized to the spleen. In addition to the recent discovery of the TCF1 + CD8 + T cell subset in the models of GvHD and Graft-versus-leukemia (GvL) 44 , 45 , Harris et al demonstrated that the loss of TCF1 in donor CD8 + T cells reduced the severity and persistence of GvHD symptoms in the MHC-mismatched GvHD model 46 . These findings suggest that the generation of the TCF1 + progenitor CD8 + T cell subset represents a common mechanism of CD8 + T cell differentiation, which plays a crucial role in sustaining antigen-specific CD8 + T cells in microenvironments with persistent antigenic stimulation, such as allo-HSCT.…”