HEB Restrains Effector Gene Expression during Early CD8⁺ Memory Precursor T Cell Differentiation

Memory T cells are essential for maintaining long-term adaptive immunity. Memory cell precursors and short-lived effector cells emerge from undifferentiated naïve T cells directly downstream of TCR signaling but little is known about how this lineage choice is regulated at the molecular level. The transcription factor HEB is known to be an important regulator of thymic T cell development, but how it functions in peripheral T cell differentiation is poorly understood. We assessed the role of HEB in the differentiation of memory-like T cell precursors by inducing TCR signaling in CD8 T cells in the context of memory-polarizing cytokines or inflammatory conditions and found that CD8 T cells from HEB-deficient mice underwent accelerated differentiation as compared to WT cells. Transcriptomic analysis revealed aberrant upregulation of immune response genes and decreased expression of genes promoting stemness from the earliest stages of post-TCR signal activation and persisting throughout the course of differentiation. In addition, acute viral infection of HEB cKO mice resulted in enhanced memory precursor cell formation and increased effector functionality. Therefore, we have identified HEB as a central participant in the gene regulatory networks that regulate early CD8 memory T cell differentiation and effector gene expression. This study showed that naïve CD8 T cells lacking HEB exhibit increased TCR signal strength and loss of signatures of stem-ness, revealing a role for HEB in promoting immune memory.