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Abstract
The expanding range of CD8 T cell phenotypes deepens the need to address how specific signals and contexts lead to this subset diversity. As lymphocytes enter the lymph node, they encounter and interact with the stromal cells that form the lymph node itself, so it’s also crucial to understand the role that lymphatic endothelial cells (LECs) of the lymph node play in adaptive immunity. Our lab has shown that at homeostasis, LEC education of naïve CD8 T cells results in a population that skews to central memory. Here, we address some of the dynamics that govern CD8 T cell memory differentiation when primed or maintained by LECs and uncover how LECs cooperate with dendritic cells (DCs) to establish a memory niche not only at homeostasis, but also at different cytokine microenvironments crucial for active immune responses. In vitro models reveal that priming of T cells by LECs stimulated under Th1 and Th2 related cytokine conditions induced a T cell population that is ~80 percent central memory in phenotype that grows generationally. Interestingly, when LECs were treated with immunosuppressive cytokines associated with the tumor microenvironment the T cells developed into an effector memory-like phenotype with reduced proliferation. At all conditions, LEC-primed CD8 T cells result in a phenotype that has stem-like qualities (Tscm) defined by high expression of TCF1 and PD1, and low expression of Tim3 when compared to those primed by DCs. LEC priming for 24 hours is sufficient to confer this phenotype, even if T cells are maintained by DCs after LEC priming. In contrast, if T cells are primed by DCs and maintained in a LEC rich environment, the resulting T cells skew towards central memory more than those primed by DCs alone. Together this shows that LECs are potent modulators of T cell phenotype in vitro which has incredible translational potential to modulate phenotypes for different immunotherapies; in particular, adoptive T cell therapies and CAR T therapies would benefit from this, as the phenotype we observe LECs developing is the desired phenotype for these therapies.