In addition, repeated injections of ␣-GalCer or the related glycolipid OCH to apolipoprotein E knockout (apoE ؊/؊ ) mice during the early phase of atherosclerosis significantly enlarged the lesion areas compared with mice injected with vehicle control. However, administering ␣-GalCer to apoE ؊/؊ mice with established lesions did not significantly increase the lesion area but considerably decreased the collagen content. Atherosclerosis development in either AD-fed WT or apoE ؊/؊ mice was associated with the presence of V␣14J␣18 transcripts in the atherosclerotic arterial walls, indicating that NKT cells were recruited to these lesions. Thioglycolate-elicited macrophages pulsed with oxidized low-density lipoproteins expressed enhanced CD1d levels and induced NKT cells to produce interferon-␥, a potentially proatherogenic T-helper 1 (T H 1) cytokine. Collectively, we conclude that NKT cells are proatherogenic in mice. IntroductionAtherosclerosis is an inflammatory vascular disease that involves components of the innate and acquired immune systems. [1][2][3] Several studies have suggested that lymphocytes, which are detected in atherosclerotic lesions in humans and mice, 4,5 play a proatherogenic role. [6][7][8] Recently, the role of distinct lymphocyte subsets in the development of atherosclerosis has been evaluated. For example, emerging evidence indicates that T-helper 1 (T H 1) cells are proatherogenic, 9 whereas T H 2 cells are antiatherogenic. 10,11 These observations are further supported by the finding that T H 1 cytokines (eg,) are important in the progression of atherosclerosis [12][13][14][15] and that, among T H 2 cytokines, IL-10 is antiatherogenic. 16 On the other hand, recent studies have suggested that B cells play a protective role in atherogenesis. 17,18 Natural killer T (NKT) cells are a unique subset of lymphocytes that have surface markers and functions of T cells and NK cells. [19][20][21][22][23] Several characteristics of NKT cells suggest that they may play a role in the atherogenic process. Most NKT cells express an invariant V␣14J␣18 T-cell receptor (TCR)-V␣ chain paired with a restricted set of TCR-V␤ chains. These classical NKT cells recognize lipid antigens presented by the major histocompatibility complex (MHC) class 1-like molecule CD1d, produce copious amounts of IFN-␥ and IL-4 on activation, 22 and constitutively express Fas-ligand. 23 Moreover, NKT cells play a protective role in several autoimmune diseases, infections, and tumor progression/ metastasis. 20 Protective effects of NKT cells and their ligands in autoimmunity are largely attributed to their capacity to promote T H 2 immune responses. 24,25 However, in some situations, NKT cells can contribute to the development of T H 1 immune responses as well. 26 Therefore, it was difficult to predict whether NKT cells would play a proatherogenic or an antiatherogenic role. 2 To date, few studies have investigated the role of CD1d and CD1d-dependent T cells in atherogenesis. CD1d-expressing cells are present in human atherosclerotic...

Transcriptional expression of a gene or genes is absolutely required for induction of glucocorticoid-induced thymocyte apoptosis. We have previously shown that expression of T cell death-associated gene 8 (TDAG8) is quickly induced exclusively in the thymus after dexamethasone (DEX) treatment. Here, we present data that TDAG8 expression is induced prior to induction of DEX-mediated apoptosis. In contrast, TDAG8 expression in thymocytes was not induced in the process of gamma-irradiation-mediated apoptosis. TDAG8 expression accelerated only DEX-induced, but not TCR-mediated or gamma-irradiation-induced, thymocyte apoptosis in transgenic mice overexpressing TDAG8. Interestingly, these effects were specifically detected in CD4(+)CD8(+) double-positive thymocytes. Moreover, activation of caspase-3, -8 and -9 was enhanced in thymocytes of TDAG8 transgenic mice after DEX stimulation. In conclusion, TDAG8 expression is involved in glucocorticoid-induced signals to activate caspase-9, -8 and -3 for subsequent apoptosis induction in CD4(+)CD8(+) double-positive thymocytes.

Abstract. Allograft inflammatory factor (AIF)-1, originally cloned from a rat heart allograft under chronic rejection, is induced in various inflammatory conditions including atherosclerosis. Using mouse AIF-1 transfected macrophages and AIF-1 transgenic (AIF-1 Tg ) mice, we analyzed the influence of AIF-1 overexpression on macrophage phagocytosis and the development of atherosclerosis. The AIF-1 transfectants showed significantly increased phagocytosis of latex beads and E. coli BioParticles as well as incorporation of acetylated low-density lipoprotein (LDL) compared to those of vector controls. Concordant results were obtained with elicited peritoneal exudate cells from AIF-1 Tg mice. When AIF-1 Tg mice were crossbred with apolipoprotein E knockout mice (ApoE -/-), these AIF-1 Tg ApoE -/-mice developed significantly increased atherosclerotic lesions compared to ApoE -/-mice. These results suggest that enhanced AIF-1 expression leads to augmented incorporation of degenerated LDL by macrophages and promotes development of atherosclerotic vasculopathy.

SUMMARYUsing murine spleen-derived dendritic cells (DC) and DO11.10 T cells specific for ovalbumin (OVA), the influences of maturational condition and antigen dose on the capability of DC to induce helper T-cell (Th) differentiation were analysed. Immature DC (iDC) with high-or low-dose OVA 323-339 predominantly induced Th1 or Th2 responses in DO11.10 T cells, respectively. DC matured by tumour necrosis factor-a (TNF/DC) induced a significantly higher Th2 response in the presence of low-dose OVA 323-339 than iDC and DC matured by lipopolysaccharide (LPS) (LPS/ DC). In the presence of high-dose OVA 323-339 , LPS/DC induced significantly lower levels of Th1 response than iDC. Under these conditions no difference in the Th1 response was noted between TNF/DC and iDC. The enhanced capability of TNF/DC with a low-dose antigen for Th2 polarization and the decreased preference of LPS/DC with a high-dose antigen to Th1 polarization were not related to the amount of IL-12 produced in these cultures. These results demonstrate for the first time that TNF/DC with a low-dose antigen are potent inducers of Th2 differentiation.

following correction should be noted. On page 2475, the second line of the left column that reads ". . . were reconstituted with aly͞aly BM cells after lethal irradiation" should read ". . . were reconstituted with aly͞ϩ BM cells after lethal irradiation."Immunology. In the article "Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation," by Beatriz Goyenechea and César Milstein, which appeared in number 24, November 26, 1996, of Proc. Natl. Acad. Sci. USA (93, 13979-13984), the following revision should be noted: The formula at the bottom of the first column of page 13980 was misprinted. The correct formula is:FIG. 6. Three-dimensional structure of rQR1 in complex with FAD and NADP ϩ (12). The C-terminal 43 amino acids (232-274) are shown in red (Left), and have been truncated at the arrow (Right). Different colors of the backbone indicate the two different subunits. It can be seen that the truncated portion of QR2 is critical for binding of the pyrophosphate moiety of the NAD(P)H cofactor. Note that the contact regions between the enzyme and FAD are presumably preserved in QR2 (Right), consistent with the tight binding of FAD. The structural comparison between rQR1 and hQR2 is appropriate since the homology between rQR1 and hQR1 is very high (85% identity). CorrectionsProc. Natl. Acad. Sci. USA 94 (1997) Contributed by Robert A. Good, January 3, 1997 ABSTRACTThe development of T cells within the thymus is largely dependent on intact cortical and medullary epithelial cells. However, it has been reported that positive selection of natural killer antigen 1.1 ؉ (NK1.1 ؉ ) T cell antigen receptor (TCR)-␣͞␤ ؉ thymocytes recently identified among CD4 ؉ 8