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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

Phenotypic characterization of NKG2C+ NK cells in TAP-deficient individuals. (A) Size of the NKG2C+NKG2A− subset in PBMCs from seven TAP-deficient donors compared to CMV− and CMV+ healthy controls. (B, C) Gating strategy and phenotype of NKG2C+NKG2A− (red lines) compared to conventional CD56dim NK cells (blue lines) after gating on live CD3−CD4−CD14−CD19−CD7+CD56dim/− cells from three TAP-deficient donors compared to one healthy control.
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Figure 1: Phenotypic characterization of NKG2C+ NK cells in TAP-deficient individuals. (A) Size of the NKG2C+NKG2A− subset in PBMCs from seven TAP-deficient donors compared to CMV− and CMV+ healthy controls. (B, C) Gating strategy and phenotype of NKG2C+NKG2A− (red lines) compared to conventional CD56dim NK cells (blue lines) after gating on live CD3−CD4−CD14−CD19−CD7+CD56dim/− cells from three TAP-deficient donors compared to one healthy control.

Mentions: To study the occurrence of expanded NK cell populations in patients lacking expression of normal levels of HLA class I molecules, we assessed the expression of NKG2C on NK cells from seven previously described TAP-deficient patients for which sufficient numbers of PBMCs were available for detailed phenotypic and functional characterization (27–31). Two of these patients (TAP#01 and TAP#02) displayed increased frequencies of NKG2A−NKG2C+ NK cells corresponding to those observed in CMV+ healthy donors (Figure 1). One patient (TAP#05) displayed an expanded but yet smaller population of NKG2A−NKG2C+ NK cells. The remaining four patients had frequencies of NKG2A−NKG2C+ NK cells in the range of those observed in CMV− healthy donors (3).


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)

Phenotypic characterization of NKG2C+ NK cells in TAP-deficient individuals. (A) Size of the NKG2C+NKG2A− subset in PBMCs from seven TAP-deficient donors compared to CMV− and CMV+ healthy controls. (B, C) Gating strategy and phenotype of NKG2C+NKG2A− (red lines) compared to conventional CD56dim NK cells (blue lines) after gating on live CD3−CD4−CD14−CD19−CD7+CD56dim/− cells from three TAP-deficient donors compared to one healthy control.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4594010&req=5

Figure 1: Phenotypic characterization of NKG2C+ NK cells in TAP-deficient individuals. (A) Size of the NKG2C+NKG2A− subset in PBMCs from seven TAP-deficient donors compared to CMV− and CMV+ healthy controls. (B, C) Gating strategy and phenotype of NKG2C+NKG2A− (red lines) compared to conventional CD56dim NK cells (blue lines) after gating on live CD3−CD4−CD14−CD19−CD7+CD56dim/− cells from three TAP-deficient donors compared to one healthy control.
Mentions: To study the occurrence of expanded NK cell populations in patients lacking expression of normal levels of HLA class I molecules, we assessed the expression of NKG2C on NK cells from seven previously described TAP-deficient patients for which sufficient numbers of PBMCs were available for detailed phenotypic and functional characterization (27–31). Two of these patients (TAP#01 and TAP#02) displayed increased frequencies of NKG2A−NKG2C+ NK cells corresponding to those observed in CMV+ healthy donors (Figure 1). One patient (TAP#05) displayed an expanded but yet smaller population of NKG2A−NKG2C+ NK cells. The remaining four patients had frequencies of NKG2A−NKG2C+ NK cells in the range of those observed in CMV− healthy donors (3).

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