Polyclonal Expansion of NKG2C+ NK Cells in TAP-deficient Patients

• Main Authors: vivien eBeziat, Marwan eSleiman, Jodie eGoodridge, Mari eKaarbo, lisa eliu, Halvor eRollag, hans-gustaf eljunggren, jacques ezimmer, Karl-Johan eMalmberg
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2015-10-01
• Series: Frontiers in Immunology
• Subjects: Adaptive Immunity; Cytomegalovirus Infections; natural killer (NK) cells; Killer cell immunoglobulin-like receptor; Transporter associated with antigen processing (TAP)
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fimmu.2015.00507/full

Adaptive natural killer (NK) cell responses to human cytomegalovirus (CMV) 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 expansion of NKG2C+ NK cells in patients with transporter associated with antigen presentation (TAP)-deficiency, whom 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. Thus, the emergence of NKG2C-responsive adaptive NK cells in TAP-deficient patients may contribute to anti-viral immunity and potentially explain these patients’ low incidence of severe viral infections.