NKG2D Supports Long Lived Effector T Cell Function 2308628

Abstract Introduction Memory CD8 T cells display heterogeneity in their phenotype and function. We have described a memory subset of CD8 T cells termed Long Lived Effector T cells (LLECs) that maintain high expression of KLRG1. LLECs maintain strong effector function and are more effective at clearing systemic infections than other memory subsets. LLECs are enriched for the expression of Natural Killer (NK) receptors on their surface compared to other memory T cells. These receptors on NK cells are classified as either activating or inhibitory, but their role on CD8 T cells has not been extensively investigated. NKG2D is highly expressed on LLECs and is an activating receptor that recognizes stress ligands. We hypothesize that the expression of activating NK receptors increases the cytotoxic capacity of LLECs in both an antigen specific manner by acting as a costimulatory receptor and allows them to respond to bystander cues in the absence of T cell receptor stimulation. Methods To address the role of NKG2D as a costimulatory molecule, we have leveraged OT-I and P14 CD8 T cells activated with cognate peptide, Ova and Gp33, respectively. We used CRISPR to ablate NKG2D on naïve T cells and blocking antibodies against NKG2D to investigate differences in response when NKG2D signals are lost. We have also utilized the “dirty mouse” model of normalized polymicrobial exposure (NME) to study the role of NKG2D in bystander responses mediated by a polyclonal memory pool. Results Our preliminary work has found that interruption of NKG2D signaling leads to reduced T cell polyfunctionality following peptide stimulation. Additionally, we find that blocking NKG2D in a NME reduced the ability of mice to clear a novel Listeria monocytogenes infection. Conclusion This work supports that NK receptors contribute to CD8 T cell responses and pathogen clearance and may be particularly relevant on LLECs as a regulator of their robust effector function. Funding Source R01AI155468 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)