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

Vivien Béziat,Jacques Zimmer,Lisa L Liu,Marwan Sleiman,Jodie P Goodridge,Hans-Gustaf Ljunggren,Mari Kaarbø,Karl-Johan Malmberg,Halvor Rollag

doi:10.3389/fimmu.2015.00507

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.

Highlights

Considerable lines of evidence indicate that human and mouse natural killer (NK) cells can undergo a phase of selective expansion in response to viral challenges [1, 2]
Expansion of NKG2C+ NK Cells in Patients with transporter associated with antigen presentation (TAP) Deficiency 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 Peripheral blood mononuclear cells (PBMCs) were available for detailed phenotypic and functional characterization [27,28,29,30,31]
Our results document the emergence of functional adaptive NKG2C+ NK cells in TAP-deficient patients

Summary

Introduction

Considerable lines of evidence indicate that human and mouse natural killer (NK) cells can undergo a phase of selective expansion in response to viral challenges [1, 2] In humans, such “adaptive” NK cell responses are typically linked to cytomegalovirus (CMV) infection, in isolation or in the context of other viral infections [3,4,5,6,7,8,9]. Hallmarks of this response include selective expansion of NKG2C+ NK cells with expression of self-HLA class I-specific killer-cell immunoglobulin-like receptors (KIRs) [3, 4, 10]. It has been suggested that NK cell interaction with HLA class I molecules is important for shaping

Methods

Results

Conclusion