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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

Adaptive NK cells from TAP-deficient patients display polyclonal KIR repertoires. Frequencies of NK cell subsets expressing seven KIRs analyzed, and the 128 possible combinations thereof, in one healthy control and three TAP-deficient individuals. The presence of one KIR in a combination is represented by a color code below the graph. The analysis is displayed for NKG2A+NKG2C− (black lines), NKG2A−NKG2C− (red lines), and NKG2A−NKG2C+ (blue lines) NK cell subsets. Patients TAP#1 and #5 are KIR haplotype B/X and patient TAP#2 is haplotype A/A.
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Figure 2: Adaptive NK cells from TAP-deficient patients display polyclonal KIR repertoires. Frequencies of NK cell subsets expressing seven KIRs analyzed, and the 128 possible combinations thereof, in one healthy control and three TAP-deficient individuals. The presence of one KIR in a combination is represented by a color code below the graph. The analysis is displayed for NKG2A+NKG2C− (black lines), NKG2A−NKG2C− (red lines), and NKG2A−NKG2C+ (blue lines) NK cell subsets. Patients TAP#1 and #5 are KIR haplotype B/X and patient TAP#2 is haplotype A/A.

Mentions: In healthy individuals, the expansion of NKG2C+ NK cells is more or less confined to subsets expressing at least one self-specific KIR (3, 4, 10). This biased expansion was recently attributed to an increased resistance to starvation-induced apoptosis in educated NK cells (12). Thus, it is possible that educated and uneducated NK cell subsets respond equally well to NKG2C ligation, but only those that express self-specific KIR tolerate the stress of cytokine withdrawal after an initial inflammatory response to acute infection, resulting in accumulation of self-specific KIR-expressing NK cells. When examining the KIR-expression profiles in TAP-deficient patients, no skewing of KIR expression among differentiated NKG2C+ NK cells was observed (Figure 2). These results show that the expression of a self-KIR does not provide any selective benefit in conditions of low HLA class I expression.


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)

Adaptive NK cells from TAP-deficient patients display polyclonal KIR repertoires. Frequencies of NK cell subsets expressing seven KIRs analyzed, and the 128 possible combinations thereof, in one healthy control and three TAP-deficient individuals. The presence of one KIR in a combination is represented by a color code below the graph. The analysis is displayed for NKG2A+NKG2C− (black lines), NKG2A−NKG2C− (red lines), and NKG2A−NKG2C+ (blue lines) NK cell subsets. Patients TAP#1 and #5 are KIR haplotype B/X and patient TAP#2 is haplotype A/A.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Adaptive NK cells from TAP-deficient patients display polyclonal KIR repertoires. Frequencies of NK cell subsets expressing seven KIRs analyzed, and the 128 possible combinations thereof, in one healthy control and three TAP-deficient individuals. The presence of one KIR in a combination is represented by a color code below the graph. The analysis is displayed for NKG2A+NKG2C− (black lines), NKG2A−NKG2C− (red lines), and NKG2A−NKG2C+ (blue lines) NK cell subsets. Patients TAP#1 and #5 are KIR haplotype B/X and patient TAP#2 is haplotype A/A.
Mentions: In healthy individuals, the expansion of NKG2C+ NK cells is more or less confined to subsets expressing at least one self-specific KIR (3, 4, 10). This biased expansion was recently attributed to an increased resistance to starvation-induced apoptosis in educated NK cells (12). Thus, it is possible that educated and uneducated NK cell subsets respond equally well to NKG2C ligation, but only those that express self-specific KIR tolerate the stress of cytokine withdrawal after an initial inflammatory response to acute infection, resulting in accumulation of self-specific KIR-expressing NK cells. When examining the KIR-expression profiles in TAP-deficient patients, no skewing of KIR expression among differentiated NKG2C+ NK cells was observed (Figure 2). These results show that the expression of a self-KIR does not provide any selective benefit in conditions of low HLA class I expression.

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