The CD44 family of surface receptors regulates adhesion, movement, and activation of normal and neoplastic cells. The cytokine osteopontin (Eta-1), which regulates similar cellular functions, was found to be a protein ligand of CD44. Osteopontin induces cellular chemotaxis but not homotypic aggregation, whereas the inverse is true for the interaction between CD44 and a carbohydrate ligand, hyaluronate. The different responses of cells after CD44 ligation by either osteopontin or hyaluronate may account for the independent effects of CD44 on cell migration and growth. This mechanism may also be exploited by tumor cells to promote metastasis formation.

The maintenance of immune homeostasis requires regulatory T cells (Tregs). Given their intrinsic self-reactivity, Tregs must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3+ CD4 and Qa-1-restricted CD8 Tregs results in defective regulatory activity and autoimmunity in mice. Helios-deficient Treg develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 Treg also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. Definition of Helios as a key transcription factor that stabilizes regulatory T-cells in the face of inflammatory responses provides a genetic explanation for a core property of regulatory T-cells.

We describe a murine cDNA, designated Early T lymphocyte activation 1 (ETA-1) which is abundantly expressed after activation of T cells. Eta-1 encodes a highly acidic secreted product having structural features of proteins that bind to cellular adhesion receptors. The Eta-1 gene maps to a locus on murine chromosome 5 termed Ric that confers resistance to infection by Rickettsia tsutsugamushi (RT), an obligate intracellular bacterium that is the etiological agent for human scrub typhus. With one exception, inbred mouse strains that expressed the Eta-1a allele were resistant to RT infection (RicR), and inbred strains expressing the Eta-1b allele were susceptible (RicS). These findings suggest that Eta-1 is the gene inferred from previous studies of the Ric locus (5). Genetic resistance to RT infection is associated with a strong Eta-1 response in vivo and inhibition of early bacterial replication. Eta-1 gene expression appears to be part of a surprisingly rapid T cell-dependent response to bacterial infection that may precede classical forms of T cell-dependent immunity.

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Background-The atheromodulating activity of B cells during the development of atherosclerosis is well documented, but the mechanisms by which these cells are regulated have not been investigated. Methods and Results-Here, we analyzed the contribution of Qa-1-restricted CD8 + regulatory T cells to the control of the T follicular helper-germinal center B-cell axis during atherogenesis. Genetic disruption of CD8 + regulatory T cell function in atherosclerosis-prone apolipoprotein E knockout mice resulted in overactivation of this axis in secondary lymphoid organs, led to the increased development of tertiary lymphoid organs in the aorta, and enhanced disease development. In contrast, restoring control of the T follicular helper-germinal center B-cell axis by blocking the ICOS-ICOSL pathway reduced the development of atherosclerosis and the formation of tertiary lymphoid organs. Moreover, analyses of human atherosclerotic aneurysmal arteries by flow cytometry, gene expression analysis, and immunofluorescence confirmed the presence of T follicular helper cells within tertiary lymphoid organs. Conclusions-This study is the first to demonstrate that the T follicular helper-germinal center B-cell axis is proatherogenicand that CD8 + regulatory T cells control the germinal center reaction in both secondary and tertiary lymphoid organs. Therefore, disrupting this axis represents an innovative therapeutic approach.

Cloned mouse mast cells resemble, by ultrastructure, immature mast cells observed in vivo. These mast cell clones can be grown in the absence of any other cells, facilitating direct investigations of their biochemistry and function. We find that cloned mast cells express plasma membrane receptors (Fc~R) that bind mouse IgE with an equilibrium constant (KA) similar to that of normal mouse peritoneal mast cells. In addition, cloned mast cells do not display detectable la antigens and cannot enhance Ig secretion when added to lymphocyte cultures or mediate natural killer lysis. In the presence of I mM sodium butyrate, cloned mast cells stop dividing and acquire abundant electron-dense cytoplasmic granules similar to those of mature mast cells. Their histamine content increases concomitant with cytoplasmic granule maturation and may exceed that of untreated mast cells by 50-fold. Unlike peritoneal mast cells, cloned mast cells incorporate 35S04 into chondroitin sulfates rather than heparin. 1-hese findings demonstrate that, unlike fully differentiated mouse peritoneal mast cells, cloned immature mouse mast cells contain no heparin and low levels of histamine. In addition, they establish that high-affinity Fc, R are expressed early in mast cell maturation, well before completion of cytoplasmic granule synthesis and mediator storage.We have previously reported methods to clone mast ceils with normal karyotypes from mouse hematopoietic tissue in vitro (30). Our cloned mast cells contain less histamine than normal mouse peritoneal mast cells and resemble immature mast cells by morphology. Others have described similar findings with uncloned cells (22,32,38,42,43,51,53). Although some mast cells synthesize heparin when fully differentiated (23, 54), certain mast cell tumors are devoid of heparin and incorporate 3BSO4 into chondroitin sulfate exclusively (18). Histochemical evidence suggests that normal immature connective tissue mast cells (6) and the mast cells in the intestinal lamina propria of rodents (25, 50) also may synthesize glycosaminoglycans other than heparin, but this notion has not been confirmed directly.In this report, we show that cloned mast cells closely resemble, by ultrastructure, immature mast cells found in vivo.Cloned mast cells incorporate 35804 preferentially into chondroitin sulfates, confirming histochemical evidence that immature mast cells contain little heparin. In addition, cloned mast cell proliferation, cytoplasmic granule synthesis, and mediator storage can be modulated in vitro, permitting direct analysis of mast cell maturation. MATERIALS AND METHODS AntiseraLyt-1.2 and Lyt-2.2 antisera, prepared as described (45), were kindly donated by F. W. Shen~; monoclonal antibody against Thy-l.2 (mc-a-Thy-l.2) was donated by Ed Clark2; and mc-a-Lyt-1 and mc-a-Lyt-2 were gifts from J. Ledbetter and L Herzenberg a. Mast cells were examined for la antigens using ATH-a-ATL alloantisera (16) or mc-a-Ia (10-3.6, reference 35) generously provided by John Freed and J. M. Kupinski 4. Mast Cells...

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