Sophia Chai

IL-15 Receptor Maintains Lymphoid Homeostasis by Supporting Lymphocyte Homing and Proliferation

The IL-15 receptor alpha subunit (IL-15Ralpha) mediates high-affinity binding of IL-15, a pleiotropic cytokine implicated in the development of innate immune cells. We have generated IL-15Ralpha null (IL-15Ralpha-/-) mice to understand the role of IL-15Ralpha in immune development and function. IL-15Ralpha-/- mice are markedly lymphopenic despite grossly normal T and B lymphocyte development. This lymphopenia is due to decreased proliferation and decreased homing of IL-15Ralpha-/- lymphocytes to peripheral lymph nodes. These mice are also deficient in natural killer cells, natural killer T cells, CD8+ T lymphocytes, and TCRgammadelta intraepithelial lymphocytes. In addition, memory phenotype CD8+ T cells are selectively reduced in number. Thus, IL-15Ralpha has pleiotropic roles in immune development and function, including the positive maintenance of lymphocyte homeostasis.

The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses

A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)–induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor–induced activity of the transcription factor NF-κB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.

Coordinate Expression and Trans Presentation of Interleukin (IL)-15Rα and IL-15 Supports Natural Killer Cell and Memory CD8+ T Cell Homeostasis

The high affinity interleukin (IL)-15 receptor, IL-15Rα, is essential for supporting lymphoid homeostasis. To assess whether IL-15Rαs role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Rα– and IL-2/15Rβ–deficient mice. We find that IL-15Rα–competent, IL-2/15Rβ–deficient cells are able to support IL-15Rα–deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Rα–mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Rα functions in vivo. Surprisingly, using IL-15– and IL-15Rα–deficient mixed chimera, we also find that IL-15 and IL-15Rα must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Rα is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Rα defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.

Interleukin (IL)-15Rα–deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–deficient Mice

Natural killer (NK) cells protect hosts against viral pathogens and transformed cells. IL-15 is thought to play a critical role in NK cell development, but its role in the regulation of peripheral NK cells is less well defined. We now find that adoptive transfer of normal NK cells into mice lacking the high affinity interleukin (IL)-15 receptor, IL-15Rα, surprisingly results in the abrupt loss of these cells. Moreover, IL-15Rα–deficient NK cells can differentiate successfully in radiation bone marrow chimera bearing normal cells. Finally, adoptively transferred IL-15Rα–deficient NK cells survive in normal but not IL-15Rα–deficient mice. These findings demonstrate that NK cell–independent IL-15Rα expression is critical for maintaining peripheral NK cells, while IL-15Rα expression on NK cells is not required for this function.

Cutting Edge: Murine Dendritic Cells Require IL-15Rα to Prime NK Cells

NK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Rα-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-γ, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Rα expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Rα and anti-IL-2Rβ but not anti-IL-2Rα-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Rα/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Rα to present IL-15 in trans to NK cells during NK cell priming.

IL-15Rα expression on CD8+ T cells is dispensable for T cell memory

The generation and maintenance of immunological memory requires the activation, expansion, and persistent proliferation of antigen-specific T cells. Recent work suggests that IL-15 may be important for this process. Surprisingly, we now find that expression of the high-affinity receptor for IL-15, IL-15Rα, on T cells is dispensable for the generation or maintenance of memory CD8+ T cells. By contrast, IL-15Rα expression on cells other than T cells is absolutely critical for this function. These findings may be related to IL-15Rαs ability to present IL-15 in trans to low-affinity IL-15Rβ/γc receptors on memory CD8+ T cells. These unexpected results provide insights into how IL-15Rα supports memory CD8+ T cells.

ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development

Proteins that directly regulate tumour necrosis factor receptor (TNFR) signalling have critical roles in regulating cellular activation and survival. ABIN-1 (A20 binding and inhibitor of NF-κB) is a novel protein that is thought to inhibit NF-κB signalling. Here we show that mice deficient for ABIN-1 die during embryogenesis with fetal liver apoptosis, anaemia and hypoplasia. ABIN-1 deficient cells are hypersensitive to tumour necrosis factor (TNF)-induced programmed cell death, and TNF deficiency rescues ABIN-1 deficient embryos. ABIN-1 inhibits caspase 8 recruitment to FADD (Fas-associated death domain-containing protein) in TNF-induced signalling complexes, preventing caspase 8 cleavage and programmed cell death. Moreover, ABIN-1 directly binds polyubiquitin chains and this ubiquitin sensing activity is required for ABIN-1’s anti-apoptotic activity. These studies provide insights into how ubiquitination and ubiquitin sensing proteins regulate cellular and organismal survival.

Interleukin-15 and the regulation of lymphoid homeostasis.

Interleukin-15 (IL-15) is a cytokine that plays unique roles in both innate and adaptive immune cell homeostasis. While early studies suggested that IL-15 resembled IL-2, more recent work suggests that IL-15 may play multiple unique roles in immune homeostasis befitting its pleiotropic expression pattern. This review will focus on recent studies that highlight some of these functions.

Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

The skin barrier is the body’s first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.

Wdr1-mediated cell shape dynamics and cortical tension are essential for epidermal planar cell polarity

During mouse development, core planar cell polarity (PCP) proteins become polarized in the epidermal plane to guide angling/morphogenesis of hair follicles. How PCP is established is poorly understood. Here, we identify a key role for Wdr1 (also known as Aip1), an F-actin-binding protein that enhances cofilin/destrin-mediated F-actin disassembly. We show that cofilin and destrin function redundantly in developing epidermis, but their combined depletion perturbs cell adhesion, cytokinesis, apicobasal polarity and PCP. Although Wdr1 depletion accentuates single-loss-of-cofilin/destrin phenotypes, alone it resembles core PCP mutations. Seeking a mechanism, we find that Wdr1 and cofilin/destrin-mediated actomyosin remodelling are essential for generating or maintaining cortical tension within the developing epidermal sheet and driving the cell shape and planar orientation changes that accompany establishment of PCP in mammalian epidermis. Our findings suggest intriguing evolutionary parallels but mechanistic modifications to the distal wing hinge-mediated mechanical forces that drive cell shape change and orient PCP in the Drosophila wing disc.