Development and Function of CD94-Deficient Natural Killer Cells

Abstract

The CD94 transmembrane-anchored glycoprotein forms disulfide-bonded heterodimers with the NKG2A subunit to form an inhibitory receptor or with the NKG2C or NKG2E subunits to assemble a receptor complex with activating DAP12 signaling proteins. CD94 receptors expressed on human and mouse NK cells and T cells have been proposed to be important in NK cell tolerance to self, play an important role in NK cell development, and contribute to NK cell-mediated immunity to certain infections including human cytomegalovirus. We generated a gene-targeted CD94-deficient mouse to understand the role of CD94 receptors in NK cell biology. CD94-deficient NK cells develop normally and efficiently kill NK cell-susceptible targets. Lack of these CD94 receptors does not alter control of mouse cytomegalovirus, lymphocytic choriomeningitis virus, vaccinia virus, or Listeria monocytogenes. Thus, the expression of CD94 and its associated NKG2A, NKG2C, and NKG2E subunits is dispensable for NK cell development, education, and many NK cell functions.

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

“…Therefore we explored how HLA-E-bound peptide can influence NK cell reactivity. [35][36][37][38][39][40][41][42][43][44] Stabilizes HLA-E but Requires HLA Class I Leader Peptides to Inhibit NKG2A + NK Cells. HCV core [35][36][37][38][39][40][41][42][43][44] (YLLPRRGPRL) is a known HLA-A2 CTL epitope that also up-regulates HLA-E expression (27).…”

“…[35][36][37][38][39][40][41][42][43][44] Stabilizes HLA-E but Requires HLA Class I Leader Peptides to Inhibit NKG2A + NK Cells. HCV core [35][36][37][38][39][40][41][42][43][44] (YLLPRRGPRL) is a known HLA-A2 CTL epitope that also up-regulates HLA-E expression (27). Therefore we investigated whether HCV core [35][36][37][38][39][40][41][42][43][44] could inhibit NK cells via NKG2A.…”

“…HCV core [35][36][37][38][39][40][41][42][43][44] (YLLPRRGPRL) is a known HLA-A2 CTL epitope that also up-regulates HLA-E expression (27). Therefore we investigated whether HCV core [35][36][37][38][39][40][41][42][43][44] could inhibit NK cells via NKG2A. To avoid the confounding effects of endogenous peptides, we used the transporters associated with antigen processing (TAP)-deficient cell line 721.174 (.174), which constitutively expresses HLA-E.…”

“…It also demonstrates that NK cells expressing inhibitory receptors from the killer cell immunoglobulin-like receptor or C-type lectin-like receptor families respond with different stoichiometries to changes in the levels of cell-surface MHC class I. Thus these two receptor families may have distinct but complementary functions in recognizing changes in MHC class I. incubated overnight with 0-100 μM of HCV core [35][36][37][38][39][40][41][42][43][44] or with the HLA-E-binding HLA-G signal peptide (HLA-G sp ,VMAPRTLFL) and were stained for cell-surface HLA-E expression. In the absence of exogenous peptide, HLA-E expression was detectable on the cell surface.…”

“…In the absence of exogenous peptide, HLA-E expression was detectable on the cell surface. Both HLA-G sp and HCV core [35][36][37][38][39][40][41][42][43][44] enhanced cellsurface HLA-E, with expression saturating at ∼100 μM ( Fig. 1 A and B).…”