KLF2-defined spatial positioning of T cells determines their susceptibility to immunoregulatory NK cells 2825

Description Emerging evidence in mice and humans indicates that natural killer (NK) cells can restrain vaccine efficacy. Specifically, vaccine-elicited antibody responses are decreased by perforin-dependent killing of a subset of activated CD4 T cells by NK cells. The translational goal of manipulating this suppressive function of NK cells to enhance vaccine responses is constrained by an incomplete understanding of how NK cells select these T cells for killing. Using single-cell transcriptomics, high-dimensional flow cytometry, and CRISPR editing, we define unique features of the CD4 T cells targeted by NK cells in mice. NK cells preferentially reduce a proliferative subset of follicular helper (Tfh)-biased CD4 T cells exhibiting a unique krüpple-like factor 2 (KLF2)-driven transcriptional program. While KLF2-high and KLF2-low T cell subsets migrate into T-cell or B-cell follicles, respectively, the KLF2-intermediate subset targeted by NK cells expresses intermediate levels of the positional mediators, integrin β7 and S1PR1, resulting in localization at the T-B interface. NK cells are transiently enriched at this same location during T-cell killing. Importantly, NK cell suppression of CD4 T cells is ameliorated by CRISPR-mediated deletion of KLF2 in T cells. Thus, transcriptionally determined spatial liaisons of NK cells and target T cells facilitate elimination a subset of developing Tfh to restrain the T-dependent B cell responses after immunization. Funding Sources Supported by AI148080, AI176519, GM063483, AI165396, HD000850, AI165396, AI148684, AR070549 and DK078392. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)