Stromal cell–derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis
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
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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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 8

Tfh and GC–B cell responses in inguinal LNs upon CIA in EC-Del1 and Del1-KO mice.

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Tfh and GC–B cell responses in inguinal LNs upon CIA in EC-Del1 and Del1...
CIA was induced by i.d. injection (into the tail) of 2 mg/mL CII emulsified with 2 mg/mL CFA (in EC-Del1 mice and WT littermates; A and B) or with 1 mg/mL CFA (Del1-KO mice and WT littermates; C–H). After 10 days, mononuclear cells from inguinal LNs were harvested and analyzed for Tfh and GC–B cell markers by FACS. (A and C) Representative FACS plots (left) and frequencies and numbers of Tfh cells defined as CD4+CD19–CXCR5+PD-1hiBCL6hi cells (right) of indicated genotypes. (B and D) Representative FACS plots (left) and frequencies and numbers of GC–B cells defined as CD4–CD19+PNA+FAS+ cells (right) of indicated genotypes. (E) On days 7, 14, 21, and 42, sera were collected from Del1-KO mice and WT littermates (same mice analyzed in Figure 1 for other parameters) and isotype-specific and total IgG Abs to CII were measured by ELISA. (F–H) 10 days after CIA induction, mononuclear cells from inguinal LNs of Del1-KO mice and WT littermates were harvested and analyzed by FACS for the indicated activation markers in Tfh cells. (F) Representative FACS plots (top) and frequencies of pSTAT3+ cells and MFI of pSTAT3 expression in Tfh (CD4+CXCR5+PD-1hi) cells (bottom). (G) Representative FACS plots (left) and frequencies of pZAP70+ cells and MFI of pZAP70 expression in Tfh (CD4+CXCR5+PD-1hi) cells (right). (H) Representative FACS plots (left) and frequencies of Ki-67+ cells in Tfh (CD4+CD19– CXCR5+PD-1hi) cells (right). Data are the mean ± SD (A–D, n = 8 mice/group; E, n = 9 mice/group; and F–H, n = 7 mice/group, all from 2 independent experiments). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Student’s unpaired t test (A–C, D left, F, and H); Mann-Whitney U test (D right, G); and 2-way ANOVA with repeated-measures and Sidak’s post tests for comparison with WT mice (E).