Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity

Böttcher, Jan; Schanz, Oliver; Wohlleber, Dirk; Abdullah, Zeinab; Debey–Pascher, Svenja; Staratschek‐Jox, Andrea; Höchst, Bastian; Hegenbarth, Silke; Grell, Jessica; Limmer, Andreas; Atreya, Imke; Neurath, Markus F.; Busch, Dirk H.; Schmitt, Edgar; Endert, Peter Van; Kolanus, Waldemar; Kurts, Christian; Schultze, Joachim L.; Diehl, Linda; Knolle, Percy A.

doi:10.1016/j.celrep.2013.02.008

Cited by 68 publications

(71 citation statements)

References 77 publications

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“…Very recent study has demonstrated signaling via TLRs induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (37). It has also been shown that liver-primed T cells are reactivated from their nonresponsive state and develop into effector CTLs upon TCR stimulation in combination with costimulatory signals via CD28 and IL-12 (38). Thus, the contribution of different liver cells, especially APCs that possess the ability to produce IL12 (such as Kupffer cells and DCs), to CD8 T cell activation during in vivo TLR stimulation needs to be further addressed.…”

Section: Discussionmentioning

confidence: 99%

TLR1/2 Ligand–Stimulated Mouse Liver Endothelial Cells Secrete IL-12 and Trigger CD8+ T Cell Immunity In Vitro

Liu

Jiang

et al. 2013

The Journal of Immunology

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Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8+ T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. In this study, we investigated whether functional maturation of LSECs can be achieved by TLR ligand stimulation and elucidated the mechanisms involved in LSEC-induced T cell immunity. We demonstrate that pretreatment of LSECs with palmitoyl-3-cysteine-serine-lysine-4 (P3C; TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce T cell immunity. Importantly, P3C stimulation caused functional maturation of Ag-presenting LSECs and enabled them to activate virus-specific CD8+ T cells. The LSEC-mediated CD8+ T cell immunity was initiated by soluble mediators, one of which was IL-12 secreted at a low but sustained level after P3C stimulation. P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.

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Section: Discussionmentioning

confidence: 99%

TLR1/2 Ligand–Stimulated Mouse Liver Endothelial Cells Secrete IL-12 and Trigger CD8+ T Cell Immunity In Vitro

Liu

Jiang

et al. 2013

The Journal of Immunology

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“…Our data suggest that other regulatory pathways might be involved, such as the engagement of PD-L1 by CD80 or signaling through CTLA-4, or additional ligands that are reported to be expressed on LEC surface, including the B and T lymphocyte attenuator molecule or the lymphocyte activation gene 3 (6). Interestingly, there may be more than one differentiation state of CD8 + T cells; apparently tolerized LSEC cross-primed CD8 + T cells (30), upon inflammatory recall, were capable of becoming effector cells, reminiscent of central memory T cell activity (56). This may also apply in steady-state LEC cross-primed CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hirosue

Vokali

Raghavan

et al. 2014

The Journal of Immunology

179

189

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Until recently, the known roles of lymphatic endothelial cells (LECs) in immune modulation were limited to directing immune cell trafficking and passively transporting peripheral Ags to lymph nodes. Recent studies demonstrated that LECs can directly suppress dendritic cell maturation and present peripheral tissue and tumor Ags for autoreactive T cell deletion. We asked whether LECs play a constitutive role in T cell deletion under homeostatic conditions. In this study, we demonstrate that murine LECs under noninflamed conditions actively scavenge and cross-present foreign exogenous Ags to cognate CD8+ T cells. This cross-presentation was sensitive to inhibitors of lysosomal acidification and endoplasmic reticulum–golgi transport and was TAP1 dependent. Furthermore, LECs upregulated MHC class I and the PD-1 ligand PD-L1, but not the costimulatory molecules CD40, CD80, or CD86, upon Ag-specific interactions with CD8+ T cells. Finally, Ag-specific CD8+ T cells that were activated by LECs underwent proliferation, with early-generation apoptosis and dysfunctionally activated phenotypes that could not be reversed by exogenous IL-2. These findings help to establish LECs as APCs that are capable of scavenging and cross-presenting exogenous Ags, in turn causing dysfunctional activation of CD8+ T cells under homeostatic conditions. Thus, we suggest that steady-state lymphatic drainage may contribute to peripheral tolerance by delivering self-Ags to lymph node–resident leukocytes, as well as by providing constant exposure of draining peripheral Ags to LECs, which maintain tolerogenic cross-presentation of such Ags.

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“…These results suggest that these T cells are tolerized. However, this T cell non-responsiveness is not a permanent state; a recent study has demonstrated that LSEC-primed CD8 + T cells not only can survive in vivo for a long time, but that they also can be reactivated through a combination of co-stimulatory signals [16 ], which reinstates their capability to protect against infections. When LSECs induce CD8 + T cell priming, this does not simply lead to the generation of T cells that are ultimately tolerized.…”

Section: Cross-presentation By Lsecs To Naïve Cd8 + T Cells Leads To mentioning

confidence: 97%

“…Although it is known that 2 Innate immunity antigen-presenting LSECs require several days to induce these memory-like T cells [16 ], it is noteworthy that there is exceedingly rapid GzmB induction in T cells in the first 18 h following contact with LSECs [21]. TCR signaling, in combination with IL-6 trans-signaling, is sufficient for this direct and rapid GzmB expression in T cells.…”

Section: Cross-presentation By Lsecs To Naïve Cd8 + T Cells Leads To mentioning

confidence: 98%

Hepatic immune regulation by stromal cells

Schildberg

Sharpe

Turley³

2015

Current Opinion in Immunology

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Liver-Primed Memory T Cells Generated under Noninflammatory Conditions Provide Anti-infectious Immunity

Cited by 68 publications

References 77 publications

TLR1/2 Ligand–Stimulated Mouse Liver Endothelial Cells Secrete IL-12 and Trigger CD8+ T Cell Immunity In Vitro

TLR1/2 Ligand–Stimulated Mouse Liver Endothelial Cells Secrete IL-12 and Trigger CD8+ T Cell Immunity In Vitro

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

Hepatic immune regulation by stromal cells

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