Polyclonal Expansion of NKG2C(+) NK Cells in TAP-Deficient Patients.
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.
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.
Vivien
V
Béziat
Luxembourg Institute of Health, House of Biohealth , Esch-sur-Alzette , Luxembourg.
Marwan
M
Sleiman
Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , Oslo , Norway ; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo , Oslo , Norway.
Jodie P
JP
Goodridge
Department of Microbiology, Oslo University Hospital , Oslo , Norway.
Mari
M
Kaarbø
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden.
Lisa L
LL
Liu
Department of Microbiology, Oslo University Hospital , Oslo , Norway.
Halvor
H
Rollag
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden.
Hans-Gustaf
HG
Ljunggren
Luxembourg Institute of Health, House of Biohealth , Esch-sur-Alzette , Luxembourg.
Jacques
J
Zimmer
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet , Stockholm , Sweden ; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital , Oslo , Norway ; The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo , Oslo , Norway.
Karl-Johan
KJ
Malmberg
adaptive immunity; cytomegalovirus infections; killer cell immunoglobulin-like receptor; natural killer cells; transporter associated with antigen processing