David L. Boone

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.

Interleukin 15 Is Required for Proliferative Renewal of Virus-specific Memory CD8 T Cells

The generation and efficient maintenance of antigen-specific memory T cells is essential for long-lasting immunological protection. In this study, we examined the role of interleukin (IL)-15 in the generation and maintenance of virus-specific memory CD8 T cells using mice deficient in either IL-15 or the IL-15 receptor α chain. Both cytokine- and receptor-deficient mice made potent primary CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV), effectively cleared the virus and generated a pool of antigen-specific memory CD8 T cells that were phenotypically and functionally similar to memory CD8 T cells present in IL-15+/+ mice. However, longitudinal analysis revealed a slow attrition of virus-specific memory CD8 T cells in the absence of IL-15 signals.This loss of CD8 T cells was due to a severe defect in the proliferative renewal of antigen-specific memory CD8 T cells in IL-15−/− mice. Taken together, these results show that IL-15 is not essential for the generation of memory CD8 T cells, but is required for homeostatic proliferation to maintain populations of memory cells over long periods of time.

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.

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.

The Pleiotropic Functions of Interleukin 15: Not So Interleukin 2-like After All

Since its discovery in 1994, IL-15 has been studied in the context of its structural cousin, IL-2 ([1][1]). Early biochemical and in vitro lymphocyte studies revealed many similarities between IL-15 and IL-2: (a) IL-2 and IL-15 constitute the only two members of a family of cytokines containing a

Regulation of lymphoid homeostasis by interleukin-15

Interleukin (IL)-15 is a member of the common gamma chain family of cytokines, and is closely related to IL-2. While these two cytokines share several important biological functions in vitro, recent mouse models have demonstrated unique roles for these two cytokines in supporting lymphoid homeostasis in vivo. IL-15 has been shown to regulate the homeostasis of both innate and adaptive immune cells, and this review will discuss several ways in which this pleiotropic cytokine may support lymphoid homeostasis.

Enteric flora and lymphocyte-derived cytokines determine expression of heat shock proteins in mouse colonic epithelial cells ☆

BACKGROUND & AIMS Inducible heat shock proteins (hsps), particularly hsp25 and hsp72, are expressed by surface colonocytes and may have a role in protecting intestinal epithelial cells against injury. This study is aimed at determining if enteric bacteria and/or immune signals regulate their physiologic expression. METHODS Intestinal hsp25, hsp72, and constitutive hsc73 expression were studied in immunodeficient RAG-1(-/-) mice and in normal mice. Mucosal permeability was measured by mannitol flux and transepithelial resistance. Hsp expression in intestinal YAMC cells was assessed after incubation with recombinant cytokines, activated lamina propria lymphocytes (LPLs), or Bacteroides fragilis. RESULTS Chronic metronidazole treatment decreases colonic mucosal hsp25 and hsp72 expression, an effect associated with increased susceptibility of mucosal barrier function to C. difficile toxin A. Hsp expression also was increased in YAMC cells incubated with B. fragilis, an effect mediated by lipopolysaccharide and other bacteria-derived factors. Colonic hsp72, but not hsp25 or hsc73, expression is decreased in RAG-1(-/-) mice. Recombinant IL-2 and other cytokines enhance YAMC hsp25 and/or hsp72 expression. Activated LPLs induce YAMC hsp expression, an effect blocked by IL-2 neutralizing antibody. CONCLUSIONS Enteric flora and mucosal lymphocytes play a role in maintaining physiologic expression of colonocyte hsp25 and hsp72.

African-Derived Genetic Polymorphisms in TNFAIP3 Mediate Risk for Autoimmunity

The TNF α-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case–control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio = 1.6, p = 0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio = 0.31, p = 0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.

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.