Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
Hui Wang, … , Triantafyllos Chavakis, George Hajishengallis
Hui Wang, … , Triantafyllos Chavakis, George Hajishengallis
Published August 17, 2021
Citation Information: J Clin Invest. 2021;131(19):e150578. https://doi.org/10.1172/JCI150578.
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Research Article Autoimmunity Inflammation

Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis

Abstract

The secreted protein developmental endothelial locus 1 (DEL-1) regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab–induced arthritis (CAIA) models. In both models, mice with endothelium-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, whereas arthritis was exacerbated in DEL-1–deficient mice. Compared with WT controls, mice with collagen VI promoter–driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response. Indeed, DEL-1 was expressed in perivascular stromal cells of the lymph nodes and inhibited Tfh and germinal center B cell responses. Mechanistically, DEL-1 inhibited DC-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells. Overall, DEL-1 restrained arthritis through a dual mechanism, one acting locally in the joints and associated with the anti-recruitment function of endothelial cell–derived DEL-1; the other mechanism acting systemically in the lymph nodes and associated with the ability of stromal cell–derived DEL-1 to restrain Tfh responses. DEL-1 may therefore be a promising therapeutic for the treatment of inflammatory arthritis.

Authors

Hui Wang, Xiaofei Li, Tetsuhiro Kajikawa, Jieun Shin, Jong-Hyung Lim, Ioannis Kourtzelis, Kosuke Nagai, Jonathan M. Korostoff, Sylvia Grossklaus, Ronald Naumann, Triantafyllos Chavakis, George Hajishengallis

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Figure 7

Lymph node stromal cell–derived DEL-1 inhibits Tfh and GC–B cell responses in vivo.

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Lymph node stromal cell–derived DEL-1 inhibits Tfh and GC–B cell respons...
(A) LN transplantation–based experimental design to study the function of LN stromal cell–derived DEL-1. Inguinal LNs of WT recipient mice were surgically replaced unilaterally by inguinal LNs from ColVI-Del1 (B–E) or Del1-KO (F–I) mice or their respective WT controls. (B–I) After 4 weeks, CIA was induced in the recipient mice by i.d. injection into the tail of 2 mg/mL CII emulsified with 2 mg/mL (B–E) or 1 mg/mL (F–I) CFA. On day 10, mononuclear cells from the transplanted inguinal LNs were harvested and analyzed for the indicated Tfh and GC–B cell markers by flow cytometry. (B and F) Representative FACS plots and (C and G) frequencies and numbers of Tfh cells defined as CD4+CD19–CXCR5+PD-1hiBCL6hi cells (left and middle) and MFI of BCL6 expression (right) in CD4+CD19–CXCR5+PD-1hi cells. (D and H) Representative FACS plots and (E and I) frequencies and numbers of GC–B cells defined as CD4–CD19+PNA+FAS+ cells. Data are the mean ± SD (n = 5–6 mice/group). *P < 0.05; **P < 0.01; ***P < 0.001. Student’s unpaired t test.