Cognate HLA absence in trans diminishes human NK cell education

Abstract

NK cells are innate lymphocytes with protective functions against viral infections and tumor formation. Human NK cells carry inhibitory killer cell Ig-like receptors (KIRs), which recognize distinct HLAs. NK cells with KIRs for self-HLA molecules acquire superior cytotoxicity against HLA- tumor cells during education for improved missing-self recognition. Here, we reconstituted mice with human hematopoietic cells from donors with homozygous KIR ligands or with a mix of hematopoietic cells from these homozygous donors, allowing assessment of the resulting KIR repertoire and NK cell education. We found that co-reconstitution with 2 KIR ligand-mismatched compartments did not alter the frequency of KIR-expressing NK cells. However, NK cell education was diminished in mice reconstituted with parallel HLA compartments due to a lack of cognate HLA molecules on leukocytes for the corresponding KIRs. This change in NK cell education in mixed human donor-reconstituted mice improved NK cell-mediated immune control of EBV infection, indicating that mixed hematopoietic cell populations could be exploited to improve NK cell reactivity against leukotropic pathogens. Taken together, these findings indicate that leukocytes lacking cognate HLA ligands can disarm KIR+ NK cells in a manner that may decrease HLA- tumor cell recognition but allows for improved NK cell-mediated immune control of a human γ-herpesvirus

Immune Control and Vaccination against the Epstein–Barr Virus in Humanized Mice

“…In contrast to these cytotoxic lymphocyte responses, humanized mice without additional modifications, like thymic stromal lymphopoietin (TSLP) overexpression [48], develop only IgM antibody responses during EBV infection, but not class-switched and affinity-matured humoral immune responses [36]. The expanding cytotoxic T and NK lymphocyte populations control EBV infection in humanized mice, because their antibody-mediated depletion increases viral loads and associated lymphoma formation [26,[49][50][51][52]. The respective CD8 + T cell populations balance inhibitory with activating co-receptor expression and retain superior cytotoxicity despite expression of the inhibitory PD-1 molecule [38].…”

Immunosuppressive FK506 treatment leads to more frequent EBV-associated lymphoproliferative disease in humanized mice

“…enhanced tumor formation [15][16][17][18]. Moreover, the adoptive transfer of EBV-specific T cells transiently controls high viremia in this model [19].…”

“…previously [18,56]. Reactions were run in duplicate on an ABI Prism 7700 Sequence Detector (Applied Biosystems).…”

Modeling Natural Killer Cell Targeted Immunotherapies

“…This could explain the abundance of immature NK cells (CD56 bright CD16 − KIR − ) and their functional defects. In line with this idea, recent publications showed improved NK cell licensing in a HIS models expressing diverse educating HLA alleles (143, 144). This approach may allow better definition of the mechanisms underlying human NK cell education in vivo .…”