期刊
JOURNAL OF HEPATOLOGY
卷 66, 期 5, 页码 978-986出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2016.12.015
关键词
LSEC; CD4 T cell help; Liver primed T cells; IL-6 trans-signaling
资金
- DFG [SFB 704, SFB TR57, SFB TR36]
- DFG (Excellence Cluster Immunosensation)
- Cluster of Excellence Inflammation at Interfaces
- [SFB841]
- [SFB877]
Background & Aims: Liver sinusoidal endothelial cells (LSECs) are prominent liver-resident antigen (cross-) presenting cells. LSEC cross-priming of naive CD8 T cells does not require CD4 T cell help in contrast to priming by dendritic cells (DC) but leads to the formation of memory T cells that is preceded by transient Granzyme B (GzmB) expression. Here we provide evidence for a so far unrecognized CD4 T helper cell function in LSEC-induced CD8 T cell activation. Methods: naive CD8 T cells and differentiated T helper 1 (T(h)1) cells were stimulated by antigen-presenting LSEC, and GzmB expression in CD8 T cells was determined by flow cytometry. To identify molecular pathways mediating this GzmB expression, mechanistic proof-of-concept experiments were conducted using stimulatory anti-CD3 antibody together with Hyper-IL-6. Results: We demonstrate that LSECs simultaneously function in antigen co-presentation to CD8 and CD4 T cells. Such copresentation revealed a function of T(h)1 cells to increase GzmB expression in CD8 T cells after LSEC but not DC cross-priming. IL-2 released from T(h)1 cells was required but not sufficient for rapid GzmB induction in CD8 T cells. T cell receptor together with IL-6 trans-signaling was necessary for IL-2 to mediate rapid GzmB induction. Conclusions: Our findings indicate that LSECs can serve as a platform to facilitate CD4-CD8 T cell crosstalk enhancing the immune function of LSECs to cross-prime CD8 T cells. IL-6 trans-signaling-mediated responsiveness for IL-2 inducing sustained GzmB expression in CD8 T cells reveals unique mechanisms of CD4 T cell help and CD8 T cell differentiation through liver-resident antigen-presenting cells. Lay summary: Our findings demonstrate that LSEC co-present antigen to CD8 and CD4 T cells and thereby enable CD4 T cell help for LSEC-priming of CD8 T cells. This CD4 T cell help selectively enhances the rapid upregulation of GzmB and effector function of LSEC-primed CD8 T cells thereby enhancing functional differentiation towards CD8 effector T cells. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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