Defining the extra-thymic role of HEB in the development of CD8+ T stem cell-like immunological memory

Abstract

Abstract The transcription factor HEB is involved in multiple stages of intrathymic T cell development, complexing with stage-specific partners to regulate different genes in a context-specific manner. Remarkably, little is known about how HEB influences the differentiation of peripheral T cells, and even less so of how the transcriptional circuitry in early T cell development may be re-invoked to generate long-lasting immunity. While T cells are detected in the periphery of HEB-deficient mice (HEB cKO), the contribution of HEB to the function of T cells upon pathogen encounter is obscure. Thus, HEB cKO mice were challenged with LCMV to determine the impact of HEB in the activation and differentiation of CD8+ T cells into effector and memory lineages. Throughout the course of infection, HEB cKO mice exhibited critical differences in their antigen-specific CD8+ response and had enhanced levels of stem cell-like memory T cells (Tscm). This implicated a role for HEB downstream of T cell activation, which we further confirmed using well-established in vitro cultures supplemented with or without Tscm-inducing cytokines. Consistently, HEB transcripts were detected in publicly available scRNA datasets from P14 transgenic mice infected with LCMV. To greater define the transcriptional pattern of HEB, and of others that orchestrate thymic T cell development in the context of peripheral T cell immunity, we will conduct a scRNA-seq comparative bioinformatic analysis of developing thymocytes to splenic LCMV-specific CD8+ T cells. This will advance our understanding of how early transcriptional cascades, like those initiated by HEB, are propagated in downstream immunological reactions, which may lead to therapies that can revitalize T cell immunity. Supported by a grant from NIH (1P01AI102853-06 ) and the The AAI Intersect Fellowship Program for Computational Scientists and Immunologists