Both naive and memory T cells undergo antigen-independent proliferation after transfer into a T cell–depleted environment (acute homeostatic proliferation), whereas only memory T cells slowly divide in a full T cell compartment (basal proliferation). We show, first, that naive and memory CD8+ T cells have different cytokine requirements for acute homeostatic proliferation. Interleukin (IL)-7 receptor(R)α–mediated signals were obligatory for proliferation of naive T cells in lymphopenic hosts, whereas IL-15 did not influence their division. Memory T cells, on the other hand, could use either IL-7Rα– or IL-15–mediated signals for acute homeostatic proliferation: their proliferation was delayed when either IL-7Rα was blocked or IL-15 removed, but only when both signals were absent was proliferation ablated. Second, the cytokine requirements for basal and acute homeostatic proliferation of CD8+ memory T cells differ, as basal division of memory T cells was blocked completely in IL-15–deficient hosts. These data suggest a possible mechanism for the dearth of memory CD8+ T cells in IL-15– and IL-15Rα–deficient mice is their impaired basal proliferation. Our results show that naive and memory T lymphocytes differ in their cytokine dependence for acute homeostatic proliferation and that memory T lymphocytes have distinct requirements for proliferation in full versus empty compartments.

T he superfamily of human Class II cytokines contains interleukin-10 (IL-10), the IL-10 -related interleukins , the interferons (IFN-␣, -␤ -, -, -, and -␥) and the interferon-like molecules IL-28A, IL-28B, and IL-29 (also referred to as lambda interferons). 1 Collectively, these molecules modulate innate and adaptive immune responses to environmental pathogens and protect the host against diseases such as cancer. The best-characterized class II cytokines are the type I interferons, whose expression is tightly regulated by viral infection. 2 After binding, these proteins induce a large set of interferonstimulated genes (ISGs) that inhibit viral replication and activate numerous downstream cellular responses involving dendritic cells, lymphocytes, and macrophages. 3 In addition to the type I interferons, viral infection also stimulates the rapid production of IL-28 and IL-29, a related, but distinct subset of the class II cytokine superfamily. 4,5 These proteins also possess potent antiviral activity; however, in contrast to the type I interferons, they bind a heterodimeric receptor consisting of the IL-28R␣ 4,5 subunit and the IL-10R␤ subunit, a receptor subunit that is also shared by IL-10, Chronic viral hepatitis is the leading cause of liver disease and may play a role in the pathogenesis of lesions characteristic of cirrhosis, hepatocellular carcinoma, and end-stage liver failure. The two major causes of chronic viral hepatitis are hepatitis B virus (HBV), a DNA-containing member of the Hepadnaviridae family that infects approximately 350 million people worldwide, 7 and hepatitis C virus (HCV), an RNA virus of the Flaviviridae family that infects approximately 170 million individuals worldwide. 8 IFN-␣ is an approved treatment for both types of chronic viral hepatitis and has demonstrated considerable clinical success. [9][10][11] However, this cytokine is ineffective for a substantial percentage of infected individ-

The activating receptor, NKG2D, is expressed on a variety of immune effector cells and recognizes divergent families of major histocompatibility complex (MHC) class I–related ligands, including the MIC and ULBP proteins. Infection, stress, or transformation can induce NKG2D ligand expression, resulting in effector cell activation and killing of the ligand-expressing target cell. The human cytomegalovirus (HCMV) membrane glycoprotein, UL16, binds to three of the five known ligands for human NKG2D. UL16 is retained in the endoplasmic reticulum and cis-Golgi apparatus of cells and causes MICB to be similarly retained and stabilized within cells. Coexpression of UL16 markedly reduces cell surface levels of MICB, ULBP1, and ULBP2, and decreases susceptibility to natural killer cell–mediated cytotoxicity. Domain swapping experiments demonstrate that the transmembrane and cytoplasmic domains of UL16 are important for intracellular retention of UL16, whereas the ectodomain of UL16 participates in down-regulation of NKG2D ligands. The intracellular sequestration of NKG2D ligands by UL16 represents a novel HCMV immune evasion mechanism to add to the well-documented viral strategies directed against antigen presentation by classical MHC molecules.

Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: blocking interleukin 18 attenuates intestinal damage

IntroductionGraft-versus-host disease (GVHD) remains an important complication after allogeneic bone marrow transplantation (BMT). Despite broadly reactive pharmacologic agents, GVHD is not uniformly avoided and immunosuppression may cause malignancy recurrence or immunodeficiency. Selective GVHD preventive approaches retaining a graft-versus-leukemia (GVL) effect are needed.Interleukin-21 (IL-21) is produced by CD4 ϩ T cells (especially T helper 17 [Th17]-producing cells) and natural killer T (NKT) cells 1 and signals through the IL-2␥c and IL-21R complex. IL-21R is expressed on hematopoietic and epithelial cells and promotes the activation, differentiation, maturation, or expansion of NK cells, B cells, CD8 ϩ and CD4 ϩ T cells, dendritic cells, and macrophages, resulting in anticancer activity. 2-5 IL-21 facilitates autoimmunity in some [6][7][8] but not all 9,10 experimental models by supporting immunoglobulin production and Th17 cell-mediated pathogenesis.Because IL-21 augments Th17 cell differentiation, indirect evidence for the role of IL-21 in GVHD pathogenesis may be derived from such GVHD studies. Whereas IL-17 and Th17 cells reduce GVHD mediated by CD4 ϩ and CD8 ϩ donor T cells, 11 Th17 cells accelerated GVHD mediated exclusively by CD4 ϩ T cells. 12 Naive CD4 ϩ T cells skewed toward a Th17 phenotype in vitro have been used to demonstrate that Th17 cells contribute to GVHD pathogenesis, especially involving the skin and lung. 13 IL-21 has been described variably as an inhibitor 14 or enhancer 15 of Th1 differentiation. IL-21 supports Th17 cell survival at the expense of regulatory T cells (Tregs), which are reciprocally controlled by Th17 cells. 16 By inhibiting naive T-cell conversion into CD4 ϩ 25 ϩ FoxP3 ϩ regulatory T cells (termed inducible Tregs, iTregs), 17,18 limiting the suppression of T-effectors (Teffs) by Tregs, and augmenting Th17 responses, 19,20 IL-21 may increase GVHD lethality.The present studies were conducted to delineate the influence of IL-21 on GVHD and GVL and to elucidate the mechanisms associated with the observed biologic effects. We show that blocking or abrogating the IL-21 signaling pathway reduced acute GVHD mortality and tissue damage in the small intestine and the colon associated with decreased frequencies of interferon ␥ (IFN␥)-producing tissue-resident donor T cells in the colonic lamina propria (LP). At the same time FoxP3-expressing Tregs, which were virtually absent in the presence of IL-21, were found at relatively high frequencies at the site of inflammation in the colon and the small intestine in the absence of IL-21. These data, which are the first to demonstrate an in vivo role for IL-21 in iTreg generation, suggested a causative role of iTregs in GVHD attenuation. This was confirmed using Teffs incapable of generating iTregs. Despite acute GVHD attenuation, we show that GVL can occur in the absence of IL-21. Lastly, we show that the perforin and IL-21 pathways are nonredundant in the context of both the GVHD and GVL settings. Methods MiceC57BL/6 (H-2 b , term...