Clinical Information

Natural killer (NK) cells are derived from pluripotent hematopoietic stem cell precursors but develop independently of the thymus. They comprise a key lymphocyte subset (approximately 10%-15% of peripheral blood mononuclear cells) and are a constituent of the innate immune system since these cells do not rearrange their germline DNA to obtain specificity. NK cells serve an important role in host defense against viral infections, as well as tumor surveillance. They are also a component of the adaptive immune response through cytokine production. NK cell functions are governed by a balance between activating receptors and inhibitory receptors.

NK cells are identified by expression of different cell-surface receptors, and they are not a homogeneous population.(1) In general, the most common combination of surface markers used to identify the majority of NK cells is the absence of CD3 (CD3-), along with expression of CD56 (neural cell adhesion molecule) and CD16 (low-affinity IgG Fc receptor-Fc gamma RIII). However, not all NK cells express the CD56 and CD16 markers uniformly and, therefore, can be divided into subsets based on expression of these 2 molecules.(2) The CD16+ CD56± (dim or negative) that are CD3- are referred to as cytotoxic NK cells, while the CD56+ (bright) CD16- NK cells are called regulatory or cytokine secreting NK cells.(3) These are not only phenotypically and functionally distinct subsets but also developmentally separate. The majority of human NK cells (approximately 90%) have dim expression of CD56 and moderate to high levels of CD16, as well as perforin and granzymes (2 proteins mediating cytolytic activity) and are therefore high in cytotoxic capability. The remaining minority (approximately 10%) of NK cells are the CD56(bright) cytokine-producing NK cells. Therefore, cytotoxicity and cytokine production are the major functions of NK cells. Cytotoxicity can be subdivided into natural cytotoxicity directed largely toward virally infected cells or tumor cells, in the absence of prior stimulation or immunization, and antibody-dependent cellular cytotoxicity (ADCC) directed against antibody-coated target cells.(4) Circulating NK cells are enriched for the CD56(dim) phenotype, while within the lymph nodes, NK cells are largely CD56(bright). This differential localization is related to the pattern of homing receptors expressed on NK cells: CD56(dim) NK cells express homing markers for inflamed peripheral sites, while CD56(bright) NK cells express receptors for secondary lymphoid organs. The majority of circulating human NK cells, which have cytotoxic function and phenotype (CD56[dim]), are CD27-, while the CD56(bright) cells are CD27+. Therefore, the absence of CD27 expression identifies cytotoxic effector cells within the mature NK cell subsets.(5)

Natural killer T (NKT) cells represent a specialized T-cell population that is distinct from conventional T cells. They express an invariant T-cell receptor (TCR) that recognizes self and bacterial glycosphingolipid antigens presented by the MHC class I-like molecule, CD1d.(11) The development of NKT cells is also unique from regular T cells, as NKT cell precursors are positively selected by CD4+CD8+ cortical thymocytes and the signaling pathways differ from the conventional T cells. Activated NKT cells rapidly produce large amounts of Th1 and Th2 cytokines that transactivate other immune components and, therefore, NKT cells are involved in both innate and adaptive immune responses.(11)

NK cell deficiencies can be present as part of a larger immunological syndrome or as an isolated deficiency. Some of the primary (monogenic) immunodeficiencies that affect NK cell function or numbers include autoimmune lymphoproliferative syndrome (ALPS) related to CASP8 (caspase 8 variants); familial hemophagocytic lymphohistiocytosis (FHL) types 2, 3, and 4 due to variants in the PFP1 (encoding perforin), UNC13D (encoding the Munc13-4 protein) and STX-11 (encoding syntaxin -11), respectively; Hermansky-Pudlak syndrome (AP3B1); Papillon-Lefevre syndrome (CTSC: cathepsin C); nuclear factor kappa-beta essential modulator deficiency (NEMO) due to variants in the IKBKG gene; severe combined immunodeficiencies due to mutations in the IL-2RG, JAK3, ADA, PNP, ADK2 genes; bare lymphocyte syndrome (TAP2 gene); X-linked inhibitor of apoptosis protein deficiency (XIAP gene); X-linked lymphoproliferative disease (XLP): XLP-1 (due to variants in the SAP gene); Griscelli syndrome (RAB27A gene); Chediak-Higashi syndrome (LYST gene); and Wiskott-Aldrich syndrome (WAS gene).(12) Patients with X-linked inhibitor of apoptosis protein (XIAP) deficiency have been variably reported as having either normal numbers of NKT cells (13) or low numbers of NKT cells.(14) The apparent discrepancy in the numbers of NKT cells is likely related to the difference in size of the sample control groups and disease stage of patients between the 2 reports. At the present time, the role of XIAP in development of NKT cells has not been clearly delineated.

The isolated NK-cell deficiencies include the absolute NK-cell deficiency (ANKD), the classic NK-cell deficiency (CNKD), and the functional NK-cell deficiency (FNKD). NK-cell function is absent in ANKD and CNKD and deficient in FNKD, while NK cells are present in the latter but absent in the former 2 conditions. NKT cells are absent only in ANKD and present in both CNKD and FNKD.(12) NK-cell dysfunction has also been reported in systemic juvenile rheumatoid arthritis and macrophage activation syndrome.(15) There is also more data emerging on the pathogenic role of NK cells in atopic and autoimmune diseases.(4)

Patients with HIV-1 show a gradual loss of NK cells that correlates with disease progression. There is a selective loss of CD56(dim) NK cells, while the numbers of CD56(bright) NK cells remain the same. There appears to be a defect in differentiation from immature CD56- NK cells to mature CD56(dim) NK cells (16), with an expansion of the former (CD56-CD16+) NK cells in HIV viremic patients.(17) Differential mobilization of NK-cell subsets has also been reported related to acute exercise, with CD56(bright) NK cells being less responsive than CD56(dim) NK cells and the ratio of CD56(bright):CD56(dim) favors the former at least up to 1-hour post-exercise.(18)

NK cells also play an important role in regulating viral infections, and their deficiency predisposes individuals to susceptibility with herpes virus infections. NKG2D expression has been reported to decrease during human cytomegalovirus infection.(19) NK cells that express inhibitory receptors to self-MHC class I molecules are called "licensed," which means they are functionally more responsive to stimulation, while "unlicensed" NK cells lack receptors for self-MHC class I and are hyporesponsive. Contrary to the hypothesis that "licensed" NK cells are key for viral immunity, the depletion of "unlicensed" NK cells impairs control of viremia, suggesting that these cells are critical for protection against viral infection.

NK-cell lymphocytosis is seen in NK-neoplasias, extranodal NK/T-cell lymphoma, aggressive NK-cell leukemia, and blastic NK-cell lymphoma. Chronic NK-cell lymphocytosis is an indolent disorder characterized by proliferation of CD3-CD56+CD16- NK cells. Epstein-Barr virus (EBV) can infect nonneoplastic NK cells(20), and there is an expansion of CD16+CD56(dim) NK cells. Chronic active EBV infection involving NK cells can present with severe inflammatory and necrotic skin reactions typically associated with EBV+ NK-cell lymphoproliferative disease.(21)