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Liver sinusoidal endothelial cell cross-priming is supported by CD4 T cell-derived IL-2.

Abstract：

BACKGROUND & AIMS:Liver sinusoidal endothelial cells (LSECs) are prominent liver-resident antigen (cross-)presenting cells. LSEC cross-priming of naïve 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:Naïve CD8 T cells and differentiated T helper 1 (Th1) 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 co-presentation revealed a function of Th1 cells to increase GzmB expression in CD8 T cells after LSEC but not DC cross-priming. IL-2 released from Th1 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.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Wittlich M,Dudek M,Böttcher JP,Schanz O,Hegenbarth S,Bopp T,Schmitt E,Kurts C,Garbers C,Rose John S,Knolle PA,Wohlleber D

doi

10.1016/j.jhep.2016.12.015

subject

Has Abstract

pub_date

2017-05-01 00:00:00

pages

978-986

issue

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(16)30748-6

journal_volume

pub_type

杂志文章

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Liver sinusoidal endothelial cell cross-priming is supported by CD4 T cell-derived IL-2.