Dendritic cells are rare haematopoietic cells that reside in a number of organs and tissues. By capturing, processing and presenting antigens to T cells, dendritic cells are essential for immune surveillance and the regulation of specific immunity. Several members of the tumour necrosis factor receptor (TNFR) superfamily are integral to the regulation of the immune response. These structurally related proteins modulate cellular functions ranging from proliferation and differentiation to inflammation and cell survival or deaths. The functional activity of dendritic cells is greatly increased by signalling through the TNFR family member CD40. Here we report the characterization of RANK (for receptor activator of NF-kappaB), a new member of the TNFR family derived from dendritic cells, and the isolation of a RANK ligand (RANKL) by direct expression screening. RANKL augments the ability of dendritic cells to stimulate naive T-cell proliferation in a mixed lymphocyte reaction, and increases the survival of RANK+ T cells generated with interleukin-4 and transforming growth factor (TGF)-beta. Thus RANK and RANKL seem to be important regulators of interactions between T cells and dendritic cells.

A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function

https://www.cell.com/immunity/pdf/S1074-7613(00)80439-2.pdf

Stat6 Is Required for Mediating Responses to IL-4 and for the Development of Th2 Cells

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

/pdf/reversible-defects-in-natural-killer-and-memory-cd8-t-cell-2meygczf1f.pdf

Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice

Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T cells. We have inactivated the IL-7 gene in the mouse germline by using gene-targeting techniques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was blocked at the transition from pro-B to pre-B cells. Thymic cellularity was reduced 20-fold, but retained normal distribution of CD4 and CD8. Splenic T cellularity was reduced 10-fold. Splenic B cells, also reduced in number, showed an abnormal population of immature B cells in adult animals. The remaining splenic populations of lymphocytes showed normal responsiveness to mitogenic stimuli. These data show that proper T and B cell development is dependent on IL-7. The IL-7-deficient mice are the first example of single cytokine-deficient mice that exhibit severe lymphoid abnormalities.

https://rupress.org/jem/article-pdf/181/4/1519/1106581/1519.pdf

Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

ULBPs, Novel MHC Class I–Related Molecules, Bind to CMV Glycoprotein UL16 and Stimulate NK Cytotoxicity through the NKG2D Receptor

We have recently cloned a novel cytokine, IL-15, with shared bioactivities but no sequence homology with IL-2. We found high affinity IL-15 binding to many cell types, including cells of non-lymphoid origin. Analysis of IL-15 interaction with subunits of the IL-2 receptor (IL-2R) revealed that the alpha subunit was not involved in IL-15 binding. We demonstrated directly in cells transfected with IL-2R subunits that both the beta and gamma chains are required for IL-15 binding and signaling. Hence, IL-15, like IL-2, IL-4 and IL-7, utilizes the common IL-2R gamma subunit found to be defective in X-linked severe combined immunodeficiency in humans. IL-15 is the only cytokine other than IL-2 that has also been shown to share the beta signaling subunit of IL-2R. The differential ability of some cells to bind and respond to IL-2 and IL-15 implies the existence of an additional IL-15-specific component.

Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15.

Interleukin 15 (IL-15) is a member of the four-helix bundle cytokine family that shares many in vitro biological activities with IL-2. Previous work demonstrated that IL-15 utilizes the beta and gamma chains of the IL-2 receptor (IL-2R), and that these are essential for IL-15-mediated signal transduction. However, several lines of evidence indicated the existence of an additional, IL-15-specific receptor component. An IL-15 binding chain was identified on a murine T cell clone, and direct expression cloning was used to isolate the corresponding cDNA. The predicted structure of this protein shows sequence similarity to the IL-2R alpha chain. Transfection of this cDNA into a murine, IL-3-dependent myeloid cell line, 32D-01, conferred IL-15 binding and, together with transfection of the IL-2R beta chain, rendered the cells responsive to IL-15 stimulation. This experiment confirmed that the IL-15 binding chain is part of the IL-15 receptor, and it is designated as the IL-15R alpha subunit. The expression pattern of the IL-15R alpha mRNA is distinct from that of IL-2R alpha mRNA. Recombinant expression of a soluble form of IL-15R alpha demonstrated that it is a potent inhibitor of IL-15 biological activity.

K H Grabstein

Papers

Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15.

Interleukin 15 and Its Receptor