Activating Receptor NKG2C Research Articles

Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus

Natural killer (NK) cells are known to mount a rapid response to several virus infections. In experimental models of acute viral infection, this response has been characterized by prompt NK cell activation and expansion followed by rapid contraction. In contrast to experimental model systems, much less is known about NK cell responses to acute viral infections in humans. We demonstrate that NK cells can rapidly expand and persist at highly elevated levels for >60 d after human hantavirus infection. A large part of the expanding NK cells expressed the activating receptor NKG2C and were functional in terms of expressing a licensing inhibitory killer cell immunoglobulin-like receptor (KIR) and ability to respond to target cell stimulation. These results demonstrate that NK cells can expand and remain elevated in numbers for a prolonged period of time in humans after a virus infection. In time, this response extends far beyond what is considered normal for an innate immune response.

The structural basis for intramembrane assembly of an activating immunoreceptor complex

Many receptors that activate cells of the immune system are multisubunit membrane protein complexes in which ligand recognition and signaling functions are contributed by separate protein modules. Receptors and signaling subunits assemble through contacts among basic and acidic residues in their transmembrane domains to form the functional complexes. Here we report the nuclear magnetic resonance (NMR) structure of the membrane-embedded, heterotrimeric assembly formed by association of the DAP12 signaling module with the natural killer (NK) cell-activating receptor NKG2C. The main intramembrane contact site is formed by a complex electrostatic network involving five hydrophilic transmembrane residues. Functional mutagenesis demonstrated that similar polar intramembrane motifs are also important for assembly of the NK cell-activating NKG2D-DAP10 complex and the T cell antigen receptor (TCR)-invariant signaling protein CD3 complex. This structural motif therefore lies at the core of the molecular organization of many activating immunoreceptors.

The activating receptor CD94-NKG2E is required for protective NK cell responses to a lethal viral infection (39.26)

Abstract The CD94/NKG2 receptors of NK cells are C-type lectin-like heterodimers formed by CD94 and inhibitory receptor NKG2A, or activating receptor NKG2C or NKG2E. However, the physiological functions of those receptors in the NK cell responses to viral infections are not clear. Ectromelia virus (ECTV) is an orthopoxvirus (OPV) that causes mousepox, the mouse equivalent of human smallpox. Previous studies have shown that NK cell responses are essential for the natural resistance of C57BL/6 (B6) mice to mousepox. Here, we show that B6 mice deficient in CD94 (CD94 KO) and B6D2-D6 mice (a B6 congenic mouse strain harboring NK complex from the DBA2/J, also deficient in CD94) succumbed to ECTV infection due to defective NK cell cytolytic activity. In addition, [B6-CD94 KOxB6D2-D6] F1 mice remained susceptible to mousepox whereas CD94 KO or B6D2-D6 mice expressing transgenic CD94 on NK cells were resistant. Together, these data demonstrated an essential role for CD94 in resistance to mousepox. To determine the specific CD94/NKG2 receptor required for resistance, we co-incubated reporter cells expressing CD94 and different NKG2 molecules with ECTV infected cells. We found that this resulted in the activation of only the reporters co-expressing CD94 and NKG2E. These results suggest that the activating receptor CD94-NKG2E mediates the protective NK cell response to ECTV. This is the first report showing the functional involvement of CD94/NKG2 receptors in an anti-viral NK cell response.

Natural killer cell receptor repertoire following HLA-matched allogeneic hematopoietic stem cell transplantation

6635 Background: Following hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells are among the first lymphocytes to recover, returning to normal levels within six weeks after HSCT. NK cells may mediate anti-tumor effects and regulate graft versus host disease (GVHD); modulation of the relative frequency and intensity of expression of the cytotoxic NK receptors may influence NK activity post transplant. Methods: We compared the NK receptor expression in seven patients at one month following non-myeloablative HLA-matched allogeneic HSCT with that of donors and healthy volunteers. NK cells were divided into two subsets based on expression of CD56 and CD16. Both subsets were assessed for three main classes of receptors that trigger or inhibit cytotoxicity: natural cytotoxicity receptors (NCR), killer immunoglobulin-like receptors (KIR) and C-type lectin receptors. Results: Compared to donors, the expression of the NCR NKp46 increased significantly in all patients, whereas NKp30 increased in the CD 56+ bright subset only in patients that developed acute GVHD. Expression of KIR receptors (CD158A, CD158B) did not change or decreased slightly. In contrast the C-type lectin receptor CD 94 was upregulated on most NK cells. The heterodimeric partners of CD94, NKG2A and NKG2C, were also increased, but the increase in frequency of cells expressing the inhibitory receptor NKG2A was greater than that of the activating receptor NKG2C. The homodimeric activating receptor NKG2D increased in all patients. No significant differences in NK receptor expression between the donors and healthy volunteers was observed Conclusions: These results demonstrate changes in the NK receptor repertoire during the early post-transplant period that may have an impact on NK cells mediated cytotoxicity. No significant financial relationships to disclose.

Natural killer cell receptor repertoire following HLA-matched allogeneic hematopoietic stem cell transplantation

6635 Background: Following hematopoietic stem cell transplantation (HSCT), natural killer (NK) cells are among the first lymphocytes to recover, returning to normal levels within six weeks after HSCT. NK cells may mediate anti-tumor effects and regulate graft versus host disease (GVHD); modulation of the relative frequency and intensity of expression of the cytotoxic NK receptors may influence NK activity post transplant. Methods: We compared the NK receptor expression in seven patients at one month following non-myeloablative HLA-matched allogeneic HSCT with that of donors and healthy volunteers. NK cells were divided into two subsets based on expression of CD56 and CD16. Both subsets were assessed for three main classes of receptors that trigger or inhibit cytotoxicity: natural cytotoxicity receptors (NCR), killer immunoglobulin-like receptors (KIR) and C-type lectin receptors. Results: Compared to donors, the expression of the NCR NKp46 increased significantly in all patients, whereas NKp30 increased in the CD 56+ bright subset only in patients that developed acute GVHD. Expression of KIR receptors (CD158A, CD158B) did not change or decreased slightly. In contrast the C-type lectin receptor CD 94 was upregulated on most NK cells. The heterodimeric partners of CD94, NKG2A and NKG2C, were also increased, but the increase in frequency of cells expressing the inhibitory receptor NKG2A was greater than that of the activating receptor NKG2C. The homodimeric activating receptor NKG2D increased in all patients. No significant differences in NK receptor expression between the donors and healthy volunteers was observed Conclusions: These results demonstrate changes in the NK receptor repertoire during the early post-transplant period that may have an impact on NK cells mediated cytotoxicity. No significant financial relationships to disclose.