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Immunoengineering

Systems Immunology

Flexible control of T cell self renewal by a reversible epigenetic switch

Friday, October 13, 2023
8:15 AM – 8:30 AM PDT
Location: 348 (Center, Level 3)
Introduction:: Self-renewing, stem-like memory T cells are key to long term protective immunity. In acute infections, T cells that maintain self-renewal capabilities persist after pathogen clearance to generate immunological memory and provide a rapid and robust response to reinfection. In long term chronic infections, or in cancer, self-renewing T cells differentiate to effector-like cells to replenish cytotoxic cells to maintain long term protection against the threat. As cytotoxic cells in the tumor microenvironment undergo exhaustion differentiation and lose effector function, maintenance of these self-renewing cells is critical to a persistent anti-tumor response. In both cases, self-renewing T cells are characterized by expression of the transcription factor TCF1. Understanding how cells regulate TCF1 expression, and thereby control their memory potential and stemness, under both acute and chronic stimulation, is crucial for therapeutic T cell strategies to provide robust and long lasting responses.

Materials and Methods:: We utilized ex vivo stimulation of CD8 T cells from a fluorescent reporter mouse for Tcf7, the gene that encodes for TCF1. We performed single cell and clonal lineage tracking by live imaging, single cell and bulk transcriptomics, bulk epigenomics, and flow cytometry to characterize the maintenance or loss of memory potential in both acute and chronic settings, ex vivo and in a B16 melanoma tumor model. We additionally utilized mathematical modeling based on our experimental results to demonstrate how memory cell population size scales with the severity of the threat depending on the mechanism of memory regulation.

Results, Conclusions, and Discussions:: We find that upon acute stimulation ex vivo, T cells can choose early whether to maintain or lose memory potential, but that effector cells can also regain lost memory potential after antigen clearance. This flexibility is conferred by stochastic and reversible epigenetic silencing of TCF1. Our mathematical models demonstrate that this flexibility is essential for memory population scaling with the severity of the pathogen and the total number of responding immune cells. We propose that this stochasticity and flexibility allows for robust responses to diverse pathogens.


To see if this flexibility was present beyond acute immune challenge, we expanded our ex vivo model from acute to chronic stimulation. We find that chronic stimulation ex vivo phenotypically matches the cell states found in the B16 melanoma model, namely the loss of TCF1 expression and upregulation of inhibitory receptors over time. We find that over time on stimulation cells transition from an initially plastic state, where they can reactivate TCF1 upon antigen withdrawal, to a more terminal state where they cannot regain memory potential upon rest. We find that this transition from a plastic to a terminal state is controlled by epigenetic repression of memory gene loci, and that small molecule inhibition of epigenetic modifying enzymes allows cells to reacquire memory potential. Our results provide a basis for therapeutic strategies to enhance the self-renewing, memory-like population in tumors.

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