Compartmentalized persistence of unconventional intestine-resident CD8⍺⍺ IEL throughout life 3477

Abstract Description CD8αα intestinal intraepithelial lymphocytes (IEL) are unconventional T cells involved in maintaining gut homeostasis. This elusive lineage remains underexplored, partly due to controversies regarding their existence in humans. To shed more light on CD8αα IEL, we conducted a studies using both mouse models and human gut tissue. Fate mapping revealed compartmentalized ontogeny and persistence patterns, where CD8aa IEL in the small intestine, but not in the colon, exhibited a disproportionately high representation of cells generated prior to sexual maturity. Early life derived CD8αα IEL were sustained into old age (over 1.5 years) in the small- but not the large intestine. Parabiosis studies indicated enhanced residency of CD8αα IEL in adult and aged animals as compared to conventional CD8αβ IEL. Guided by findings from our microbially enriched (“dirty”) mouse colonies – a model that better mimics adult human immune responses than SPF mice – we identified a population of CD8αα IEL in the human intestine. Encouraged by these discoveries, we sought to develop tools to study CD8αα IEL more comprehensively and established culture conditions to maintain CD8αα IEL ex vivo. In addition, single-cell analysis of > 250 surface markers employing machine learning uncovered a surface marker that, when targeted, depleted CD8αα but not CD4 or CD8αβ IEL. Our findings illuminate the significance of CD8αα IEL, suggesting its potential as a target for immunotherapeutic or vaccination strategies. Funding Sources National Health and Medical Research Council, Australia (NHMRC, APP2008853) Topic Categories Mucosal and Regional Immunology (MUC)