NK and NK/T cells in human senescence
Introduction
Human natural killer (NK) cells are populations of heterogeneous lymphocytes that are a critical complement of the innate immune response against a broad variety of infections and tumors. Although NK cell function overlaps in certain aspects with T cell function, they are components of the natural immune system together with polymorphonuclear cells and macrophages. NK cells were originally identified as a population of large granular lymphocytes, able to spontaneously lyse certain susceptible tumor cell lines without pre-sensitization or MHC restriction. Target cell lysis takes place by a secretory mechanism via exocytosis of cytoplasmic granules containing perforins that damage membrane and granzyme that damages DNA, or by a non secretory mechanism via Fas-Fas Ligand interaction used by activated NK cells. Although originally described as cytotoxic cells, involved in innate immunity and early defense, recent studies in NK cell biology, showing that NK cells express a number of cytokine receptors and that they secrete immunoregulatory cytokines, support their relevance in the regulation of the Ag specific-response [1].
NK cells are derived from pluripotent hematopoietic stem cells. A committed precursor for T and NK cells expressing FcγRIII has been demonstrated both in human and mice. This NK/T progenitor gives rise to α/β T lymphocytes when transferred intrathymically, whereas NK cells develop in the bone marrow [2], [3]. Furthermore, NK cell development requires the presence of interleukin (IL)-15, most likely produced by the bone marrow stromal cells. IL-15 is also responsible for the expression of CD56 and CD94/NKG2A inhibitory receptors during NK development, but it is not sufficient for the induction of CD16 or other Ig-like inhibitory receptors. In various culture systems stem cell factor, IL-7 and flt-ligand enhanced the IL-15 expansion of NK cells, supporting that IL-15 is the dominant factor involved in NK cell differentiation [4], [5].
NK cells do not rearrange immunoglobulin (Ig) or TCR genes and therefore, neither Ig nor the TCR/CD3 complex are expressed at the cell surface [except for the zeta (ζ) chain]. The most characteristic phenotypic markers of human NK cells are CD56, an isoform of the neural cell adhesion molecule (N-CAM), and CD16, the low affinity IgG Fc receptor (FcRγIIIA) [6], [7]. Other NK cell markers are CD57, an oligosaccharide antigenic determinant, CD2 that, besides being an adhesion molecule, is an antigen which appears on the surface of NK cells during the maturation and seems to be correlated with the acquisition of fas ligand-mediated cytotoxicity [8], NKRP1 a C-lectin type glycoprotein and CD94, also a C-lectin type invariant glycoprotein, that associates with NKG2 products [7], [9]. Although the mechanisms used by NK cells to discriminate between susceptible and resistant target cells are not fully understood, evidence showing that NK cells express both activating and inhibitory receptors support that the cytolytic function of NK cells is the result of a balance between activating and inhibitory signals delivered by these receptors [7], [10]. Several NK activation receptors capable of triggering NK cell cytotoxicity and coupled to signal transduction molecules have been defined. Thus the ζ chain is used by CD16 [11], CD2 [12] and p46 [13] whereas the HLA specific activation receptors p50 and CD94/NKG2C, as well as NKp44 are coupled to DAP12 [14], [15], [16]. Other NK receptors that also trigger NK cytolysis are CD69 [17], [18] and NKRP1 [19]. NK cells also express inhibitory receptors specific for MHC class I molecules that possess immunoreceptor tyrosine-based inhibitory motifs (ITIM) in the cytoplasmic domains. Recruitment of the SH2-containing protein tyrosine phosphatases, SHP-1 and SHP-2, by these receptors results in inhibition of cytotoxicity and cytokine secretion [20], [21], probably by inducing de-phosphorylation of the SLP-76 adaptor protein [22]. Two distinct families of receptors for MHC class I molecules have been defined. The first includes inhibitory receptors with one to four extracellular immunoglobulin domains such as p58 (CD158a, CD158b), p70 (NKB1) and p140 which interact with specific amino acids in the 77-83 region of the HLA alleles [10], [23], [24]. The second family of NK receptors are C-type lectin heterodimers composed of CD94 covalently associated with NKG2A or B [9] and recognize HLA-E molecules associated with peptides derived from the leader sequence of other HLA antigens [25], [26], [27].
NK cell function is not restricted to cytotoxicity of tumor or virally infected cells but, on the contrary, it plays a critical role in the initiation of the adaptive response. Thus, innate cytokines released after infection can activate NK cells, inducing the production of IFN-γ, TNF-α and GM-CSF, as well as chemokines, MIP-1β and RANTES. NK cells express receptors for a number of cytokines and chemokines and, therefore, they respond to a variety of stimuli. It is well known that IL-2 activates NK cells both by promoting proliferation and by enhancing cytotoxicity. Resting NK cells express the type I receptor for IL-15 (that has in common with the IL-2 receptor the β and γ chains) and it has been shown that IL-15 supports in vitro survival of NK cells and is an NK-cell chemoattractant and activator [4], [28]. IL-15 also synergizes with IL-12 to produce IFN-γ, TNF-α and GM-CSF. Furthermore the enhancement of NK cytotoxicity observed in herpesvirus infection is mediated by IL-15 induction [29]. IL-12 is also a very potent inducer of IFN-γ production by NK cells [30]. IL-18 is another monokine recently described as a powerful inducer of IFN-γ and some chemokines (alone or in combination with IL-12 or IL-15) [31] and activator of cytolytic activity by increasing perforin mediated lysis [32]. Interferons α and β also enhance NK cytotoxicity against a broad variety of, otherwise resistant, tumor cell lines. Furthermore, NK cell possess chemokine receptors CCR2 and CCR5 that not only favor NK cell migration but also NK-target cell binding and NK recruitment and it has been shown that MIP-1α, MIP-1β, MCP-1,2,3 and RANTES induce NK chemotaxis in vitro [33], [34].
Therefore, different cytokine and chemokine patterns are induced in NK cells by different co-stimulatory signals, suggesting that cytokine production from NK cells may be differently regulated in part by the monokine induced during the early pro-inflammatory response to infection and by the subset of NK cells present at the site of inflammation. These immunoregulatory cytokines and chemokines will subsequently modulate the adaptive response mediated by Th lymphocytes. Taken together, the broad range of NK cell activators and responses provide good evidence supporting the importance of NK cells in the early response against infections in co-operating in the innate response and promoting the downstream adaptive response.
Section snippets
Relevance of NK cells in the defense against infections in the elderly
The importance of NK cells in early response against infections was originally demonstrated in murine models by showing that, after NK depletion, animals were more susceptible to a wide variety of viral infections. It has also been shown that NK cells are rapidly activated and produce IFN-γ as a consequence of viral infection. This response occurs very rapidly, within hours or days, whereas the T or B cell response takes more than one week to develop. As demonstrated in mice following primary
Effect of aging on NK cell number and phenotype
The study of the human immune response in healthy elderly donors has shown that immunosenescence not only affects the T cell response, but also different aspects of innate immunity [46], [47], [48], [49]. In particular, the capacity of NK cell cytotoxicity has been extensively analyzed [47], [50]. Although original reports indicated that NK cytotoxicity could be either decreased or not affected by aging, more recent studies have demonstrated alterations in the number, phenotype and function of
Effect of aging on NK cell cytotoxicity
The cytotoxic capacity of NK cells has been extensively analyzed in elderly people and with the introduction of strict criteria to select only the very healthy elderly to analyze the effect of senescence on the immune system, it was found that NK cell cytotoxicity from peripheral blood lymphocytes is not significantly affected by aging [41], [57], [58]. However, Facchini et al. [51] and Mariani et al. [59] demonstrated that circulating NK cells from elderly subjects have a decreased cytotoxic
Effect of aging on NK cell response to cytokines
Cytokine activation of NK cells results in enhanced cytotoxicity, proliferation and synthesis and release of cytokines and chemokines. The influence of aging on the effect of IL-2 on different NK cell functions has been studied in the elderly. In vitro activation of NK cells with IL-2 or other cytokines enhances killing of NK sensitive targets (i.e. K562) and induces killing of NK resistant target cells (i.e. Daudi). The cytotoxic activity of NK cells induced by activation with IL-2, IL-12 or
NK/T cells and aging
A subset of T cells sharing characteristics with NK cells has been defined in mice. These cells now termed NK/T cells, express the NK1.1 marker and are found at high frequencies in liver. They are αβ T lymphocytes with a restricted TCR repertoire commonly expressing Vα14/Jα281, that interact the MHC class I like CD1 molecules bound to non-peptidic ligands. NK/T cells are thought to be extrathymic T cells, they respond to CD3, NK1.1 or IL-12 stimulation, produce IL-4 and have a central role in
Concluding remarks
Immunosenescence, the deterioration of the immune response associated with aging, is characterized not only by a defective T cell response but also by the number and function of other cells of the innate immune system. NK cells play a significant role in the defense against infections as a consequence of both their cytotoxic capacity and the cytokines produced, in particular IFN-γ. Age-associated alterations have been demonstrated in NK cells (Fig. 1). Thus, although NK cell cytotoxicity
Acknowledgements
Support for the work from the author’s laboratory discussed here came from Fondo Investigación Sanitaria (FIS 98/1052) and Junta de Andalucı́a (Spain) to RS, from MURST (60% fund) and University of Bologna to EM and from the European Commission (BMHI-CT94-1209; project EUCAMBIS).
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