IL-21: A New Regulator of NK Cell Activity

The innate immune system is made up of cells that might be considered "first responders" to a variety of microbial challenges. The cells are varied in type and participate both in an immediate, non-specific response to a foreign element and the development of a learned and remembered specific immune response.1,2 Among the cells traditionally considered "innate" are macrophages, mast cells, neutrophils, and dendritic cells. In addition, there is a subset of lymphocytes termed natural killer (NK) cells that were first identified based on their ability to lyse select tumor cell lines in an MHC-unrestricted manner.3,4 Although considered lymphocytes, NK cells do not express a T cell receptor or CD3 but do possess an intrinsic ability to engage in perforin-mediated cytolysis. Numerous functions are attributed to NK cells. Among these are the regulation of T cell responses through cytokine production, the stimulation of innate phagocytes via IFN-gamma secretion, and the destruction of virally-infected cells via granzyme and perforin release.5, 6

NK cells may be derived from CD34+ stem cells in the bone marrow. Flt-3 Ligand and SCF may upregulate the IL-15 R on NK progenitor cells. Progenitor cells then become responsive to bone marrow fibroblasts expressing membrane-bound IL-15, an interaction that drives stem cells into the NK cell lineage.7,8 Subsequent steps in NK cell development are in dispute. Some suggest that NK cells go through a series of maturation steps, beginning with a CD56- CD161+ IL-13++ CD16- IFN-gamma- phenotype, and ending with a CD56+ CD161- IL-13- CD16+ IFN-gamma++ phenotype.9 Others suggest that terminal differentiation results in two subsets of NK cells. One subset is immunoregulatory in nature and is characterized as CD56+++/bright, CD94+, CD62L+, CD16+/-. This population can serve as either an IL-13 secretor (if IL-15 is present) or an IFN-gamma producer (if IL-12 is present). The other subset is cytotoxic in nature and is characterized by a CD56+/dim, CD94+/-, CD16++ phenotype.10

Figure 1.IL-21 acts to prevent activation of NK cells, promote CD16 expression and IFN-gamma secretion of activated NK cells, and initiate apoptosis in differentiated NK cells.

Regardless of the exact differentiation pathway, it appears that the newly discovered cytokine IL-21 is critically involved in terminal differentiation decisions. IL-21 is a 15 kDa, four alpha-helix cytokine most closely related to IL-15.11 IL-21 is secreted by activated CD4+ T cells as part of the normal immune response to foreign antigen. Thus, it appears during the "adaptive (dendritic cell-T cell) phase" of the immune response and after the initiation of the innate response. At this point, NK cells have been activated (by Flt-3 Ligand, IL-4, IL-12, and IL-15) but not terminally differentiated. IL-21 may influence NK cells in at least three ways. First, it promotes the upregulation of CD16, the low affinity IgG receptor involved in antibody-dependent cellular cytotoxicity. Second, it induces the secretion of IFN-gamma, which acts to potentiate macrophage killing. Third, it blocks the further recruitment of uninvolved NK cells and initiates a delayed apoptosis program for already activated, terminally-differentiated NK cells, thus ensuring prompt resolution of the innate response.12,13 In summary, IL-21 would seem decisive to end-stage NK cell activity both by optimizing function and orchestrating elimination.


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