Type-1 regulatory T cells are critical for curative immunotherapy outcomes

Abstract IL-10 producing CD4 +type-1 regulatory T cells (Tr1) mediate immune tolerance during chronic infection, autoimmunity, and transplantation. We previously demonstrated that eomesodermin (Eomes) promotes Tr1 cell (Eomes +IL-10 +) development after allogenic bone marrow transplantation (alloBMT). Here we define the differentiation trajectory of functional states therein. Eomes −IL-10 −, −and +subsets (defined by mCherry GFP expression respectively) were FACS sorted alloBMT transferred into secondary recipients. +T stable in phenotype transfer while −T subset differentiated +Tr1 cells. was associated with progressive enrichment for cytotoxicity (Perforin, Nkg7, Granzyme K, Tnfrsf9), (IR) (Tim-3, Lag3, Tox, Nr4a2) chemokine (Ccl3, Ccl4, Ccl5) RNA expression. Equivalent IR, cytotoxic cytokine/chemokine confirmed at a protein level. The conditional deletion prevented resulted impaired vivo, accumulation donor CD11c +dendritic cells, mixed chimerism leukemia relapse, consistent critical role this lineage tolerance, engraftment graft-versus-leukemia effects. from CD19-targeted chimeric antigen receptor (CAR) reduced molecule (perforin, granzyme A/B) CAR escape due to CD19 loss In sum, Eomes-dependent function are curative immunotherapy outcomes.