HEB factors restrain proliferation and effector gene programming in stem cell-like memory CD8 T cells

Stem cell-like memory CD8 T cells are essential for maintaining long-term immunological memory. These cells arise directly downstream of TCR signaling during the primary immune response and persist by self-renewal. To understand how these cells are generated, we examined the role of HEB factors in memory T cell differentiation using HEB-deficient mice. In memory-polarizing cultures, CD8 T cells from HEB-deficient mice exhibited enhanced proliferation and accelerated memory T cell differentiation. Transcriptomic analysis revealed aberrant upregulation of immune response genes and decreased expression of genes promoting stem-ness in HEB-deficient cells. HEB-deficient mice also exhibited more abundant short-lived effector cells in response to a viral infection. However, these perturbations were not observed at later time points, and stem-like memory T cells were more abundant after infection in HEB-deficient mice. Consequently, manipulating HEB activity in T cell expansion cultures could hold significant promise for improving the effectiveness of immunotherapy. Overall design: To investigate the role of HEB in CD8 T cell differentiation, WT and HEB cKO CD8+ naïve, stem-cell like memory (SCM), central memory (CM), and effector/effector memory (EM) T cells were generated in vitro with CD3/CD28 stimulation + IL-7 & IL-15 for 2 days and rested for one. Cells were then sorted and RNA was extracted for downstream sequencing with two biological duplicates per cell type pooled from independent experiments.