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Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients.

Béziat V, Sleiman M, Goodridge JP, Kaarbø M, Liu LL, Rollag H, Ljunggren HG, Zimmer J, Malmberg KJ - Front Immunol (2015)

Bottom Line: We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels.Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production.The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 , Paris , France ; Imagine Institute, University Paris Descartes , Paris , France.

ABSTRACT
Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C(+) NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C(+) NK cell expansions. We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C(+) NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C(+) NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C(+) NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.

No MeSH data available.


Related in: MedlinePlus

NKG2C is functional in TAP-deficient adaptive NK cells. (A) NK cells from healthy donors (average of four donors) and three TAP-deficient patients (TAP#01, TAP#02, and TAP#05) were stimulated with the indicated targets. RAJI cells were coated with anti-CD20 (rituximab, 1 μg/mL). NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets were monitored for degranulation (CD107a) and cytokine production (IFN-γ and TNF-α). (B) Redirected ADCC assay using agonistic mAb against NKG2C. Degranulation (CD107a, top panel), IFN-γ (middle panel), and TNF-α (bottom panel) responses by the NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets are displayed. The mean and standard deviation of four representative healthy controls tested simultaneously with the three TAP-deficient patients is shown.
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Figure 4: NKG2C is functional in TAP-deficient adaptive NK cells. (A) NK cells from healthy donors (average of four donors) and three TAP-deficient patients (TAP#01, TAP#02, and TAP#05) were stimulated with the indicated targets. RAJI cells were coated with anti-CD20 (rituximab, 1 μg/mL). NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets were monitored for degranulation (CD107a) and cytokine production (IFN-γ and TNF-α). (B) Redirected ADCC assay using agonistic mAb against NKG2C. Degranulation (CD107a, top panel), IFN-γ (middle panel), and TNF-α (bottom panel) responses by the NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets are displayed. The mean and standard deviation of four representative healthy controls tested simultaneously with the three TAP-deficient patients is shown.

Mentions: It has been well documented that NK cells are hyporesponsive in TAP-deficient patients (17, 19–21), potentially due to inadequate HLA class I-mediated education. Therefore, we next set out to assess whether this hyporesponsiveness extended also to adaptive NK cells in these patients. Accordingly, we stimulated NK cells with K562 cells, RAJI cells alone, or RAJI cells coated with anti-CD20 (rituximab) and monitored polyfunctional responses in NKG2A+NKG2C− and NKG2A−NKG2C+ NK cell subsets (Figure 4A). Although responses of NK cells from the three TAP patients with evidence of polyclonal NK cell expansions differed somewhat, the patterns were clearly distinct from those of NK cells from normal donors. Both conventional and expanded NK cells from TAP-deficient patients were generally hyporesponsive to K562 stimulation and produced cytokines, albeit at low levels, in response to any stimulation. Notably, TAP-deficient NK cells responded to ADCC, in line with the ability of CD16 ligation to partly overcome the need for education (33) (Figure 4A).


Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients.

Béziat V, Sleiman M, Goodridge JP, Kaarbø M, Liu LL, Rollag H, Ljunggren HG, Zimmer J, Malmberg KJ - Front Immunol (2015)

NKG2C is functional in TAP-deficient adaptive NK cells. (A) NK cells from healthy donors (average of four donors) and three TAP-deficient patients (TAP#01, TAP#02, and TAP#05) were stimulated with the indicated targets. RAJI cells were coated with anti-CD20 (rituximab, 1 μg/mL). NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets were monitored for degranulation (CD107a) and cytokine production (IFN-γ and TNF-α). (B) Redirected ADCC assay using agonistic mAb against NKG2C. Degranulation (CD107a, top panel), IFN-γ (middle panel), and TNF-α (bottom panel) responses by the NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets are displayed. The mean and standard deviation of four representative healthy controls tested simultaneously with the three TAP-deficient patients is shown.
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Related In: Results  -  Collection

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Show All Figures
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Figure 4: NKG2C is functional in TAP-deficient adaptive NK cells. (A) NK cells from healthy donors (average of four donors) and three TAP-deficient patients (TAP#01, TAP#02, and TAP#05) were stimulated with the indicated targets. RAJI cells were coated with anti-CD20 (rituximab, 1 μg/mL). NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets were monitored for degranulation (CD107a) and cytokine production (IFN-γ and TNF-α). (B) Redirected ADCC assay using agonistic mAb against NKG2C. Degranulation (CD107a, top panel), IFN-γ (middle panel), and TNF-α (bottom panel) responses by the NKG2C+NKG2A− and NKG2C−NKG2A+ NK cell subsets are displayed. The mean and standard deviation of four representative healthy controls tested simultaneously with the three TAP-deficient patients is shown.
Mentions: It has been well documented that NK cells are hyporesponsive in TAP-deficient patients (17, 19–21), potentially due to inadequate HLA class I-mediated education. Therefore, we next set out to assess whether this hyporesponsiveness extended also to adaptive NK cells in these patients. Accordingly, we stimulated NK cells with K562 cells, RAJI cells alone, or RAJI cells coated with anti-CD20 (rituximab) and monitored polyfunctional responses in NKG2A+NKG2C− and NKG2A−NKG2C+ NK cell subsets (Figure 4A). Although responses of NK cells from the three TAP patients with evidence of polyclonal NK cell expansions differed somewhat, the patterns were clearly distinct from those of NK cells from normal donors. Both conventional and expanded NK cells from TAP-deficient patients were generally hyporesponsive to K562 stimulation and produced cytokines, albeit at low levels, in response to any stimulation. Notably, TAP-deficient NK cells responded to ADCC, in line with the ability of CD16 ligation to partly overcome the need for education (33) (Figure 4A).

Bottom Line: We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels.Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production.The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163 , Paris , France ; Imagine Institute, University Paris Descartes , Paris , France.

ABSTRACT
Adaptive natural killer (NK) cell responses to human cytomegalovirus infection are characterized by the expansion of NKG2C(+) NK cells expressing self-specific inhibitory killer-cell immunoglobulin-like receptors (KIRs). Here, we set out to study the HLA class I dependency of such NKG2C(+) NK cell expansions. We demonstrate the expansion of NKG2C(+) NK cells in patients with transporter associated with antigen presentation (TAP) deficiency, who express less than 10% of normal HLA class I levels. In contrast to normal individuals, expanded NKG2C(+) NK cell populations in TAP-deficient patients display a polyclonal KIR profile and remain hyporesponsive to HLA class I-negative target cells. Nonetheless, agonistic stimulation of NKG2C on NK cells from TAP-deficient patients yielded significant responses in terms of degranulation and cytokine production. Thus, while interactions with self-HLA class I molecules likely shape the KIR repertoire of expanding NKG2C(+) NK cells during adaptive NK cell responses in normal individuals, they are not a prerequisite for NKG2C(+) NK cell expansions to occur. The emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to antiviral immunity and potentially explain these patients' low incidence of severe viral infections.

No MeSH data available.


Related in: MedlinePlus