Immediate antigen‐specific effector functions byTCR‐transgenic CD8<sup>+</sup> NKT cells

Wingender, Gerhard; Berg, Martina; Jüngerkes, Frank; Diehl, Linda; Sullivan, Barbara A.; Kronenberg, Mitchell; Limmer, Andreas; Knolle, Percy A.

doi:10.1002/eji.200535461

Cited by 17 publications

(17 citation statements)

References 69 publications

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“…CD8 ϩ NK1.1 ϩ T cells in myosin heavy chain class I-restricted TCR-transgenic animals exhibit rapid antigen-specific effector functions (48). In the present study, LI, but not SI, CD11c ϩ CD8 ϩ T cells were frequently NK1.1 ϩ , perhaps related to intestinal microbial-derived antigenic stimulation.…”

Section: Cd3supporting

confidence: 47%

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Fujiwara

Chen

Wei

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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CD8ϩ T cells suppress CD4 ϩ T cell-induced immune colitis. Am J Physiol Gastrointest Liver Physiol 300: G939 -G947, 2011. First published March 24, 2011 doi:10.1152/ajpgi.00032.2010.-The large (LI) and small intestine (SI) differ in patterns of susceptibility to chronic mucosal inflammation. In this study, we evaluated whether this might, in part, reflect differences in resident mucosal CD11c ϩ T cells. These cells comprised 39 -48% (SI) and 12-17% (LI) of the intraepithelial compartment, most of which were T-cell receptor-␣␤ ϩ . In the SI, the majority of these cells were CD103ϩ CD8 ϩ NK1.1 Ϫ , whereas the opposite phenotype prevailed in the LI. In transfer models of CD4 ϩ T cell-induced colitis, small numbers (2.5 ϫ 10 5 ) of SI CD11c ϩ CD8 ϩ T cells suppressed proinflammatory cytokine-producing CD4 ϩ T cells in mesenteric lymph nodes and mucosa-associated lymphoid compartments (SI and LI) and protected mice from chronic inflammation. On a per-cell basis, the regulatory function of SI CD11c ϩ T cells in CD4 ϩ T cell colitis was potent compared with other reported regulatory CD4 ϩ or CD8 ϩ T cells. In contrast, neither LI CD11c ϩ T cells nor SI CD11c Ϫ T cells were effective in such immunoregulation. SI CD11c ϩ CD8 ϩ T cells were similarly effective in suppressing CD4ϩ CD45RB hi T cell colitis, as evidenced by inhibition of intracellular proinflammatory cytokine expression and histological inflammation. These findings indicate that SI CD11c ϩ

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Section: Cd3supporting

confidence: 47%

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Fujiwara

Chen

Wei

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We applied an in vivo cytotoxicity assay that has been used to study conventional CD8 + T cells (31) and tg NKT cells (28) for the investigation of the antigen-specific cytotoxicity of i NKT cells. To generate targets, whole splenocytes were loaded in vitro with αGalCer or incubated with medium as a control, differentially labeled with CFSE, injected i.v.…”

Section: Resultsmentioning

confidence: 99%

“…Yet few studies addressed the antigen-specificity of this cytotoxicity. We previously demonstrated antigen-specific cytotoxicity by transgenic, non-Vα14 i -expressing CD8 + NKT ( tg NKT) cells (28). However, little is known about the properties of and requirements for antigen-specific cytotoxicity by i NKT cells (24, 29, 30).…”

Section: Introductionmentioning

confidence: 99%

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Antigen-Specific Cytotoxicity by Invariant NKT Cells In Vivo Is CD95/CD178-Dependent and Is Correlated with Antigenic Potency

Wingender

Krebs

Beutler

et al. 2010

The Journal of Immunology

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121

107

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Invariant NKT (iNKT) cells are a unique subset of T lymphocytes that rapidly carry out effector functions following activation with glycolipid Ags, such as the model Ag α-galactosylceramide. Numerous studies have investigated the mechanisms leading to Th1 and Th2 cytokine production by iNKT cells, as well as the effects of the copious amounts of cytokines these cells produce. Less is known, however, about the mechanisms of iNKT cell cytotoxicity. In this study, we investigated the effect of Ag availability and strength, as well as the molecules involved in iNKT cytotoxicity. We demonstrate that the iNKT cell cytotoxicity in vivo correlates directly with the amount of CD1d expressed by the targets as well as the TCR affinity for the target glycolipid Ag. iNKT cells from spleen, liver, and thymus were comparable in their cytotoxicity in vitro. Surprisingly, we show that the Ag-specific cytotoxicity of iNKT cells in vivo depended almost exclusively on the interaction of CD95 (Fas) with CD178 (FasL), and that this mechanism can be efficiently used for tumor protection. Therefore, unlike NK cells, which rely mostly on perforin/granzyme-mediated mechanisms, the Ag-specific cytotoxicity of iNKT cells in vivo is largely restricted to the CD95/CD178 pathway.

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“…The liver appears to be involved in this process: first, tumor cells circulating in the blood stream are either trapped in the hepatic sinusoidal circulation due to the small vessel diameter or are arrested through mutual interaction with hepatic endothelial cells [2,44]; second, Kupffer cells, the large population of hepatic NK cells and liver endothelial cells itself have potent anti-tumor activity leading to killing of tumor cells trapped in the liver [5, 25,45]; third, apoptotic tumor cell material is eliminated locally in the liver by APC (Fig. 2) [24].…”

Section: Discussionmentioning

confidence: 99%

Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8⁺ T cell tolerance

Berg¹,

Wingender

Djandji

et al. 2006

Eur J Immunol

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Development of tumor-specific T cell tolerance contributes to the failure of the immune system to eliminate tumor cells. Here we report that hematogenous dissemination of tumor cells followed by their elimination and local removal of apoptotic tumor cells in the liver leads to subsequent development of T cell tolerance towards antigens associated with apoptotic tumor cells. We provide evidence that liver sinusoidal endothelial cells (LSEC) remove apoptotic cell fragments generated by induction of tumor cell apoptosis through hepatic NK1.1 + cells. Antigen associated with apoptotic cell material is processed and cross-presented by LSEC to CD8 + T cells, leading to induction of CD8 + T cell tolerance. Adoptive transfer of LSEC isolated from mice challenged previously with tumor cells promotes development of CD8 + T cell tolerance towards tumor-associated antigen in vivo. Our results indicate that hematogenous dissemination of tumor cells, followed by hepatic tumor cell elimination and local crosspresentation of apoptotic tumor cells by LSEC and subsequent CD8 + T cell tolerance induction, represents a novel mechanism operative in tumor immune escape. IntroductionThe liver is often a site of tumor metastasis once tumor cells reach the circulation. In particular for tumors arising in the gastrointestinal tract, the liver represents the first vascular bed that allows tumor seeding or promotes tumor elimination. The molecular mechanisms involved in tumor cell adhesion within the liver have been partly elucidated and are critical in the initiation of metastasis [1]. There is mutual interaction between liver sinusoidal cells and tumor cells, which involves the mannose receptor, release of IL-1b and IL-18 as well as endothelial cell up-regulation of adhesion molecules such as VCAM-1 [2], which all favor the development of hepatic metastasis.At the same time, hepatic sinusoidal cell populations contribute to tumor defense. Kupffer cells as the hepatic macrophage population have the capacity to kill tumor cells efficiently through phagocytosis [3] and induction Immunomodulation * These authors contributed equally to this work. ** These authors are co-senior authors.Correspondence: Percy A. Knolle [7]. These cells efficiently eliminate metastasizing tumor cells through induction of apoptosis through TRAIL, CD95L or the perforin/granzyme B pathway [8][9][10][11]. The hepatic overall capacity to eliminate tumor cells seems to be linked to the physiological role of the liver to eliminate gut-derived material from portal venous blood, because the hepatic activity of tumor cell killing is reduced in germ-free mice [12]. Furthermore, the liver is known to remove activated T cells from the circulation. Bone marrowderived as well as organ-resident hepatic cell populations attract circulating activated T cells employing CD54/CD106 and induce T cell apoptosis [13][14][15]. This similarity in retention and elimination of tumor cells and activated T cells suggests that not only may similar molecular mechanisms be employed, but also t...

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Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Cited by 17 publications

References 69 publications

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Antigen-Specific Cytotoxicity by Invariant NKT Cells In Vivo Is CD95/CD178-Dependent and Is Correlated with Antigenic Potency

Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8⁺ T cell tolerance

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Immediate antigen‐specific effector functions byTCR‐transgenic CD8+ NKT cells

Cited by 17 publications

References 69 publications

Small intestine CD11c+CD8+T cells suppress CD4+T cell-induced immune colitis

Small intestine CD11c+CD8+T cells suppress CD4+T cell-induced immune colitis

Antigen-Specific Cytotoxicity by Invariant NKT Cells In Vivo Is CD95/CD178-Dependent and Is Correlated with Antigenic Potency

Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8+ T cell tolerance

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Immediate antigen‐specific effector functions byTCR‐transgenic CD8⁺ NKT cells

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Small intestine CD11c⁺CD8⁺T cells suppress CD4⁺T cell-induced immune colitis

Cross‐presentation of antigens from apoptotic tumor cells by liver sinusoidal endothelial cells leads to tumor‐specific CD8⁺ T cell tolerance