IntroductionApoptosis is a crucial process in the development and homeostasis of multicellular organisms. 1,2 In the immune system, an enormous number of cells undergo apoptosis during development of lymphocytes and after interaction with antigens. 3 Because apoptotic cells and secondary necrotic cells releasing intracellular contents could be autoantigens, phagocytes such as macrophages and dendritic cells (DCs) must engulf these dying cells rapidly and efficiently to prevent detrimental inflammatory responses and autoimmunity. 1,4 To engulf apoptotic cells, macrophages use a variety of molecules, including Mer tyrosine kinase (MerTK), 5 milk fat globule-EGF-factor 8 (MFG-E8), 6 brainspecific angiogenesis inhibitor 1 (BAI1), 7 and T-cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4). 8,9 However, their relative contributions to the phagocytosis remain to be elucidated. Multiple receptors may simultaneously recognize multiple "eat-me" signals on apoptotic cells. In addition, different subsets of macrophages may use different repertoires of receptors for the phagocytosis.DCs are able to not only phagocytose apoptotic cells but also present dying cell-associated antigens with MHC class I molecules, which is termed as "cross-presentation." 1,10 It has been considered that, in steady state, cross-presentation of selfantigens by DCs stimulates CD8 ϩ T cells to proliferate abortively, resulting in their deletion, which is crucial to maintain peripheral tolerance. [10][11][12][13][14] Among mouse splenic DC subsets, CD8 ϩ DCs are unique in their ability for efficient phagocytosis of apoptotic cells and cross-presentation. 15,16 However, the mechanism for the recognition of apoptotic cells by CD8 ϩ DCs is poorly understood. Scavenger receptor CD36 and mannose receptor (MR)/DEC205 are highly expressed on CD8 ϩ DCs, but not CD8 Ϫ DCs, however, these receptors are not required for cross-presentation of cell-associated antigens by this DC subset. [16][17][18] Neither ␣ v ␤ 3 nor ␣ v ␤ 5 integrin that mediates phagocytosis of apoptotic cells by macrophages 1 is essential for phagocytosis by CD8 ϩ DCs. 17 Thus, the phagocytic receptor for apoptotic cells linked to cross-presentation remains to be identified.Tim-3 has been identified as a Th1-specific marker, and several in vivo studies have shown that Tim-3 regulates autoimmunity. 19,20 We and others have reported that Tim-3 negatively regulates Th1-mediated inflammatory diseases such as experimental autoimmune encephalomyelitis (EAE), type I diabetes, and acute graftversus-host diseases (aGVHD). [21][22][23] Moreover, it has been reported that Tim-3 promotes tolerance induction. 21,22 Recently, Zhu et al have identified galectin-9 as a Tim-3 ligand, and they have demonstrated that galectin-9 binds to the carbohydrate chains on Tim-3, and induces cell death of Th1 cells in vitro, which may explain the mechanism by which Tim-3 suppresses Th1 immunity. 24 On the other hand, Anderson et al have reported that Tim-3 is expressed on DCs, and that galectin-9 activate...

The glucocorticoid-induced TNF receptor (GITR), which is a member of the TNF receptor family, is expressed preferentially at high levels on CD25+CD4+ regulatory T cells and plays a key role in the peripheral tolerance that is mediated by these cells. GITR is also expressed on conventional CD4+ and CD8+ T cells, and its expression is enhanced rapidly after activation. In this report we show that the GITR provides a potent costimulatory signal to both CD25+ and CD25− CD4+ T cells. GITR-mediated stimulation induced by anti-GITR mAb DTA-1 or GITR ligand transfectants efficiently augmented the proliferation of both CD25−CD4+ and CD25+CD4+ T cells under the limited dose of anti-CD3 stimulation. The augmentation of T cell activation was further confirmed by the enhanced cell cycle progression; early induction of the activation Ags, CD69 and CD25; cytokine production, such as IL-2, IFN-γ, IL-4, and IL-10; anti-CD3-induced redirected cytotoxicity; and intracellular signaling, assessed by translocation of NF-κB components. GITR costimulation showed a potent ability to produce high amounts of IL-10, which resulted in counter-regulation of the enhanced proliferative responses. Our results highlight evidence that GITR acts as a potent and unique costimulator for an early CD4+ T cell activation.

The B7 family member B7-H3 (CD276) plays important roles in immune responses. However, the function of B7-H3 remains controversial. We found that murine B7-H3 specifically bound to Triggering receptor expressed on myeloid cells (TREM)-like transcript 2 (TLT-2, TREML2). TLT-2 was expressed on CD8 + T cells constitutively and on activated CD4 + T cells. Stimulation with B7-H3 transfectants preferentially up-regulated the proliferation and IFN-γ production of CD8 + T cells. Transduction of TLT-2 into T cells resulted in enhanced IL-2 and IFN-γ production via interactions with B7-H3. Blockade of the B7-H3:TLT-2 pathway with a mAb against B7-H3 or TLT-2 efficiently inhibited contact hypersensitivity responses. Our results demonstrate a direct interaction between B7-H3 and TLT-2 that preferentially enhances CD8 + T cell activation.

Peyer’s patch (PP) dendritic cells (DCs) have been shown to exhibit a distinct capacity to induce cytokine secretion from CD4+ T cells compared with DCs in other lymphoid organs such as the spleen (SP). In this study, we investigated whether PP DCs are functionally different from DCs in the SP in their ability to induce Ab production from B cells. Compared with SP DCs, freshly isolated PP DCs induced higher levels of IgA secretion from naive B cells in DC-T cell-B cell coculture system in vitro. The IgA production induced by PP DCs was attenuated by neutralization of IL-6. In addition, the induction of IgA secretion by SP DCs, but not PP DCs, was further enhanced by the addition of exogenous IL-6. Finally, we demonstrated that only PP CD11b+ DC subset secreted higher levels of IL-6 compared with other DC subsets in the PP and all SP DC populations, and that PP CD11b+ DC induced naive B cells to produce higher levels of IgA compared with SP CD11b+ DC. These results suggest a unique role of PP CD11b+ DCs in enhancing IgA production from B cells via secretion of IL-6.

Monoaddition of Grignard reagents, in particular tri(organo)silylmethylmagnesium chlorides, to [60]fullerene took place smoothly in the presence of dimethylformamide to produce (organo)(hydro)[60]fullerenes, C60R(1)H, in good yield (up to 93% isolated yield). The hydrofullerene was then deprotonated to generate the corresponding anion, C60R(-), which was then alkylated to obtain 58pi-electron di(organo)[60]fullerenes, C60R(1)R(2), in good to high yield (up to 93% overall yield). The two-step methodology provides a wide variety of 1,4-di(organo)[60] fullerenes bearing the same or different organic addends on the [60] fullerene core. By changing the addends, one can control the chemical and physical properties of the compounds at the molecular and bulk levels.