This article provides a brief description of the importance of NK and NKT cells in innate immunity and the influence these cells have on the adaptive immune response. Defects in NK and NKT cells often lead to autoimmune disease or increased susceptibility to infectious diseases. It is important to note that this article highlights only a subset of JAX® Mice strains with defects in innate immunity. Many other inbred strains and strains with genetic mutations with defects in NK or NKT cells are available.
The immune system of vertebrates is composed of two major components: innate immunity and adaptive immunity(1). Innate immunity provides a swift response against infectious agents prior to the initiation of adaptive immune responses. The innate response is almost immediate and is based on cells and soluble mediators equipped with germ line encoded receptors that recognize common molecular patterns on infectious agents, cells infected with viruses and transformed cells. Cells involved in innate immune responses include macrophages, dendritic cells, mast cells, neutrophils, eosinophils, natural killer (NK) cells and natural killer T (NKT) cells.
In contrast, adaptive immune responses are mediated by T lymphocytes and B lymphocytes bearing highly specific receptors that are generated by random rearrangement of gene segments and other mechanisms to generate diversity. This results in a vast array of antigen-specific receptors clonally distributed on T and B cells(2). Unlike the innate immune response, adaptive responses are not immediate, requiring three to five days for clonal expansion and differentiation of effector lymphocytes. However, adaptive responses are exquisitely specific for antigens on pathogens and have memory so that subsequent encounters with the same pathogen provoke an earlier and more robust response.
NK cells are functionally characterized by their ability to kill certain tumor cells without prior sensitization and to produce pro-inflammatory cytokines, especially interferon gamma (IFN γ), following activation. In some strains of mice, NK cells (and NKT cells) are defined by expression of a cell surface marker, NK1.1, that is recognized by monoclonal antibodies (3). NK cells develop in the bone marrow, lack rearranged T cell receptors (TCR), and develop and function normally in Prkdcscid mutant mice(4), as well as Rag1 and Rag2 deficient mice(5, 6) which are unable to rearrange TCR genes.
A unique subset of T cells, designated NKT cells, express the NK1.1 marker, as well as other typical NK receptors and upon stimulation through their TCR, rapidly produce substantial amounts of cytokines especially IL4. Unlike NK cells, NKT cells develop in the thymus and express a rearranged TCR. In contrast to typical T cells, NKT cells respond to antigen presented by the atypical MHC Class I molecule, CD1D, and express intermediate levels of TCR. In addition, NKT cells are either CD4+ or CD4-CD8-, in contrast to typical CD8+ Class I restricted T cells. Most notably, NKT cells express an extremely limited T cell repertoire, since their TCR is composed almost exclusively of V alpha 14/J alpha 281paired with beta 8, V alpha 7, or V alpha 2(7, 8) that bind lipids, glycolipids, or highly hydrophobic peptides presented by CD1D molecules(9, 10).
Increasing evidence suggests that NK and NKT cells are essential not only for defense against pathogens, but also for the initiation of adaptive immune responses and in regulating autoimmune responses. Alterations in the number or function of NKT cells have been associated with human systemic sclerosis (11), insulin-dependent diabetes mellitus (12), and spontaneous autoimmune diseases in mice (13-15). NK cells play a critical role in the early defense against infectious agents. The role of NK cells in anti-viral innate immune responses has been well documented (16).
Mouse models with alterations in the level or function of NK or NK T cells are important in defining the role of these cells in susceptibility or resistance to various infectious diseases and autoimmune disorders such as experimental autoimmune encephalomyelitis (EAE) or type I diabetes. A body of evidence suggests that NK and NKT cells regulate adaptive immune responses by the cytokines they produce after exposure to antigen (2). CD4+ T helper (Th) cell responses are polarized toward Th1 by the presence of IFN γ; whereas IL4 predisposes them toward Th2 T cell responses. Following immunization with myelin antigens, the inflammation and de-myelination in the central nervous system present in EAE is thought to be due to CD4+ Th1 cells, whereas Th2 responsive cells appear to be protective. The high susceptibility of SJL/J mice to EAE correlates with reduced numbers of NK cells leading to reduced amounts of IL4 (17). Further studies showed that SJL/J mice have a reduced number of NK1.1+ cells as well as a defect in the production of IL4 following engagement of appropriate receptors (18). Likewise, the development of spontaneous insulin-dependent autoimmune diabetes mellitus in nonobese diabetic (NOD) mice correlates with defects in the numbers and function of NKT cells (15, 19).
Other strains that have spontaneous or induced mutations that result in defects in the development or function of NK or NKT cells serve as important tools to determine the contribution of the affected cell type or function to protective or autoimmune responses. Mice homozygous for the beige-J spontaneous mutation (Lystbg-J) have abnormal giant lysosomal granules in all tissues with granule-containing cells, including lymphocytes. NK and NKT cells in mice with the beige mutation have defective natural killing capability. However, other functions of these cells, such as cytokine production, are intact (20, 21). Incomplete loss of function is also found in perforin or granzyme B-deficient mice in which natural killing capability is absent (22, 23), but other functions are likely to be intact. In all three of the previous models with defective NK or NKT cell activity, the defect is not complete and it is not specific, since CD8+ cytolytic T cells also experience defective cytolytic activity (22, 23).
Cell surface expression of MHC class I (including CD1D) is dependent on association with Beta 2 microglobulin (B2m). Since Class I proteins are essential for the maturation of conventional Class I restricted CD8+ cytolytic T cells and Cd1d restricted NKT cells, mice homozygous for the null mutation of B2m have severe depletion of both conventional CD8+ T cells, as well as NKT cells. In this case there is an almost complete deletion of NKT cells, but the deletion is not specific. Complete and specific deletion of the NKT population is obtained in mice that are homozygous for the Cd1d targeted mutation (24). However, NK cells are unaffected.
Mice homozygous for the severe combined immunodeficiency mutation (Prkdcscid) or null mutations in recombination activating genes (Rag1 or Rag2) are deficient in functional T cells and B cells and are suitable recipients for allogeneic and xenogeneic tissues. However, combining genes that cause severe combined immunodeficiency with an inbred strain that has defects in innate immunity results in an enhanced mouse model for transplantation of human cells and tissues; five-fold higher levels of human hematolymphoid engraftment has been demonstrated in NOD.CB17-Prkdcscid mice compared to CB17-Prkdcscid mice(25-29). NOD mice homozygous for both the Prkdcscid and the B2m targeted mutations support greatly elevated levels of human cell engraftment. After transfer of human peripheral blood mononuclear cells, NOD.Cg-Prkdcscid B2mtm1Unc had 6 to 7 fold higher levels of human CD4+ T cells than NOD.CB17-Prkdcscid and greater than 50 fold higher levels than CB17-Prkdcscid (30).
Authors in bold are Jackson Laboratory Scientists