Sustained innate interferon is an essential inducer of tertiary lymphoid structures
crossref(2024)
摘要
Tertiary lymphoid structures (TLS) resemble follicles of secondary lymphoid organs and develop in non-lymphoid tissues during inflammation and cancer. Which cell types and signals drive the development of TLS is largely unknown.
To investigate early events of TLS development in the lungs, we repeatedly instilled p(I:C) plus ovalbumin (Ova) intranasally. This induced TLS ranging from lymphocytic aggregates to organized and functional structures containing germinal centers. We found that TLS development is independent of FAP+ fibroblasts, alveolar macrophages or CCL19 but crucially depends on type I (IFN-I)-but not type III interferon (IFN-III)-signaling.
Mechanistically, IFN-I initiates two synergistic pathways that culminate in the development of TLS. On the one hand, IFN-I induces lymphotoxin (LT)α in lymphoid cells, which stimulate stromal cells to produce the B-cell-attracting chemokine CXCL13 through LTβR-signaling. On the other hand, IFN-I is sensed by stromal cells that produce the T-cell-attracting chemokines CXCL9, CXCL10 as well as CCL19 and CCL21 independently of LTβR. Consequently, B-cell aggregates develop within a week, whereas follicular dendritic cells and germinal centers appear after 3 weeks.
Thus, sustained production of IFN-I together with an antigen is essential for the induction of functional TLS in the lungs.
![Figure][1]
### Competing Interest Statement
The authors have declared no competing interest.
* BSA
: bovine serum albumin
DT
: diphtheria toxin
DTR
: diphtheria toxin receptor
E-TLS
: early TLS
FAP
: fibroblast activation protein
FDC
: follicular dendritic cell
HEV
: high-endothelial venule
IFN
: interferon
IFNAR1
: interferon-alpha receptor 1
IFNLR
: interferon-lambda receptor
IgG
: immunoglobulin G
i.n.
: intranasal
i.p.
: intraperitoneal
LT
: lymphotoxin
LTβR
: lymphotoxin-beta receptor
MVA
: modified vaccinia virus Ankara
Ova
: ovalbumin
PBS
: phosphate-buffered saline
PFL-TLS
: primary-follicle-like TLS
p(I:C)
: polyinosinic:polycytidylic acid
SD
: standard deviation
SFL-TLS
: secondary-follicle-like TLS
SLO
: secondary lymphoid organ
TLS
: tertiary lymphoid structure
[1]: pending:yes
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