The current model used to define T cell export from the thymus suggests that emigrating lymphocytes seed the peripheral organs as functionally mature cells. This model holds true for the majority of T cells exported from the thymus with the exception of invariant NK T (iNKT) cells. iNKT cells undergo lineage expansion after positive selection and acquire NK receptor expression once fully mature; yet, the majority of mature iNKT cells are retained in the thymus by an as of yet unidentified mechanism. In this study we demonstrate that mature iNKT cells are retained in the thymus by the chemokine receptor CXCR3. We propose that the expression of CXCR3 ligands in the thymic medullary epithelium promotes the chemotactic retention of mature iNKT thymocytes and prevents leakage of iNKT cells into the peripheral circulation
Natural killer (NK) T cells using an invariant V␣14 (V␣14i) T cell receptor rearrangement form a distinct immunoregulatory T cell lineage. Several studies indicated that a NK1.1 ؊ V␣14i NKT precursor cell differentiates and expands within the thymus before export to the peripheral tissues occurs. However, little is known about the signals that cause the emigration of V␣14i NKT cells from the thymus to the periphery. Here we show that signaling of lymphotoxin (LT) ␣ through the LT receptor (LTR) is indispensable for regulating peripheral but not thymic V␣14i NKT cell numbers. Homing to and homeostatic proliferation of thymic V␣14i NKT cells in peripheral organs, however, was not dependent on LTR. Instead, our data indicate that a LTR-expressing thymic stromal cell regulates the thymic emigration of V␣14i NKT cells but not conventional T cell receptor ␣ cells.ymphotoxin (LT) ␣ and  are members of the TNF family that form biologically active homotrimers or heterotrimers. LT␣ can be secreted as a homotrimer that can bind with equal affinity to either TNF receptor 1 or 2 (1). LT␣ can also be membrane-bound by association with LT to form LT␣ (2, 3). This heterotrimer binds exclusively to another receptor, the LT receptor (LTR), which is expressed on nonlymphoid cells (4). Over the past years, a wealth of data has indicated an indispensable role for the LT␣-LTR interaction in secondary lymphoid organ structure development and function (5, 6). In addition, some studies have shown a functional impairment in generating secondary antibody responses to certain antigens in LT-deficient mice, although normal numbers of T and B cells are found (7,8).Natural killer (NK) T cells recognize glycolipid antigens (9, 10), and they form a unique lymphocyte subset with important immunoregulatory properties (11). They coexpress NK receptors and intermediate levels of T cell receptor (TCR) ␣ and have a phenotype reminiscent of activated T cells. Several distinct subsets of NKT cells have been described (12). In mice the most abundant NKT cell subpopulation is characterized by an invariant TCR␣ rearrangement, V␣14-J␣18, and is reactive with CD1d, a nonclassical class I antigen-presenting molecule (13,14). We will hereafter refer to these cells as V␣14 invariant (V␣14i) NKT cells. Upon recognition of the synthetic glycolipid ␣-galactosylceramide (␣-GalCer), which is presented by CD1d (10), TCR stimulation results in the rapid production of proinflammatory cytokines that influence other immune cells, including NK cells, dendritic cells, and B and T cells (11).There is evidence that V␣14i NKT cells form a separate T cell lineage because they are selected in the thymus by a hematopoietic cell type, which contrasts with the selection of conventional T cells by thymic epithelial cells (15)(16)(17)(18). With the availability of ␣-GalCer-loaded CD1d tetramers (19), important new information has been obtained about V␣14i NKT cell ontogeny, showing that NK1.1 receptor expression is modulated during development, meaning that not all V␣...
The present study aimed to demonstrate the release of a retinal relaxing factor (RRF) from the retina of mice and to investigate the identity of the RRF. Ring segments of a mouse aorta were mounted in a small vessel myograph. The relaxing influence of mouse retinal tissue was assessed by placing a retina in close proximity to the precontracted aorta. This elicited reliable and reproducible relaxations in the aorta. Both the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine and the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one had no effect on the RRF response. Also the cyclooxygenase inhibitors indomethacin and sodium diclofenac failed to affect the retina-induced relaxations. Acute hypoxia largely enhanced retina-induced relaxations. It is concluded that mouse retinal tissue releases an RRF, that the mouse RRF response is not mediated by NO or prostanoids and that the mouse RRF response is profoundly influenced by hypoxia.
IntroductionLymphotoxin ␣ (LT␣), LT, and tumor necrosis factor ␣ (TNF␣) are structurally related cytokines belonging to the TNF ligand superfamily. 1 In soluble forms, LT␣ and TNF␣ homotrimers interact with TNF receptor I and II, leading to a variety of inflammatory responses. [2][3][4] LT␣ can also form a membrane-bound LT␣ 1  2 heterotrimer that signals through the LT receptor (LTR). 3,4 LIGHT, another member of the TNF superfamily, has also been identified as a ligand for the LTR. 5 While LT␣ and LT are expressed in activated lymphocytes and natural killer (NK) cells, 6 the expression of LTR is restricted to nonlymphoid cells, including bone marrow (BM) stromal cells. 7 Previous studies in mice deficient for LT␣, LT, and LTR have shown a profound role for LT-LTR-mediated signaling in the secondary lymphoid organogenesis and function. Since lymph node development is not impaired in severe combined immunodeficient (SCID), double-negative recombination-activating gene 1 (RAG1 Ϫ/Ϫ ) and RAG2 Ϫ/Ϫ mice, it has been assumed that NK progenitor cells, which express LT␣ 1  2 , are essential in secondary lymphoid formation. [8][9][10] NK cells represent an important component of the innate immune system and are able to lyse a variety of virally infected cells and tumor cells without prior sensitization. 11 Inhibitory and stimulatory receptors expressed on the surface of NK cells regulate NK cell cytotoxicity. In the mouse, the inhibitory receptors for major histocompatibility complex (MHC) class I molecules include the Ly49 and CD94/NKG2 receptor family (reviewed in Lanier 12 and Raulet et al 13 ). The signals inducing Ly49 receptor expression are poorly characterized, but BM stromal cells are indispensable for Ly49 receptor expression in vitro, [14][15][16] and an intact BM microenvironment is required for complete NK cell maturation in vivo. 17 Studies have shown that NK cell development and maturation are severely impaired in LT␣ Ϫ/Ϫ and LTR Ϫ/Ϫ mice, with reduced NK cell percentages in spleen, BM, and blood. 8,[18][19][20] However, because of higher leukocyte numbers in spleen and blood, 18,19 it is not always clear whether there was a similar reduction in the absolute NK cell number. Functionally, NK cells showed a reduced lytic capacity in vitro and an impaired antitumor function and recruitment of NK cells to lung and liver in vivo. 19 It has been indicated that the defect in NK cell development may primarily be due to defective BM stromal cells. 20 A model for the role of LT-LTR-mediated signaling in NK cell differentiation in BM has been proposed: contact of membrane-bound LT␣ 1  2 -expressing hematopoietic progenitor cells with BM stromal cells activates the latter, which in turn induce interleukin 15 (IL-15) receptor expression on NK precursor cells. IL-15 is sufficient for the IL-15-responsive precursors to differentiate into immature NK1.1 ϩ NK cells independent of BM stromal cells. Later on, BM stromal cells are, by an unidentified mechanism, required for the differentiation 20 Since NK cell...
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