Abstract
Heart failure (HF) is a leading cause of morbidity and mortality. Studies in animal models and individuals with HF revealed a prominent role for CD4+ T cell immune responses in the pathogenesis of HF and highlighted an active cross-talk between cardiac fibroblasts and interferon (IFN)-γ-producing CD4+ T cells that results in profibrotic myofibroblast transformation. Whether cardiac fibroblasts concomitantly modulate pathogenic cardiac CD4+ T cell immune responses is unknown. Here we report that mouse cardiac fibroblasts express major histocompatibility complex type II (MHCII) in two different experimental models of cardiac inflammation. We demonstrate that cardiac fibroblasts take up and process antigens for presentation to CD4+ T cells via MHCII induced by IFN-γ. Conditional deletion of MhcII in cardiac fibroblasts ameliorates cardiac remodeling and dysfunction induced by cardiac pressure overload. Collectively, we demonstrate that cardiac fibroblasts function as antigen-presenting cells and contribute to cardiac fibrosis and dysfunction through MHCII induced by IFN-γ.
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All data used to generate figures are included in the accompanying files.
Change history
09 November 2022
A Correction to this paper has been published: https://doi.org/10.1038/s44161-022-00179-6
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Acknowledgements
These studies were supported by NIH grants R01 HL123658 and R01 HL144477 (to P.A.), NIH T32 HL 69770, NIH T32AI007077-34, NIH F31HL140883 and the American Heart Association grant 18PRE34020084 (to N.N.), NIH R01 HL141187 and HL142624 (to J.D.) and NIH T32AG066574 (to D.B.).
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N.N. designed and conducted experiments, analyzed data and wrote the manuscript. K.K., R.B., S.P. and B.T. planned and conducted experiments. C.G. and M.A.P. contributed to experiment design and intellectually contributed to data analysis. M.A. performed the TAC surgeries and contributed to experiment design. J.D. and D.B. performed TAC and immunofluorescence in Tcf21iCre/+; R26eGFP mice, sorted GFP+ cardiac fibroblasts and intellectually contributed to the manuscript. P.A. overviewed the design and interpretation of all studies and wrote the paper.
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Extended data
Extended Data Fig. 1 Cardiac fibroblasts express MHCII in vivo in response to acute T. cruzi infection.
(A) Wt mice were inoculated with 20,000 T. cruzi parasites by intraperitoneal injection and the hearts were harvested at 19 days post-infection. (B-E) Ventricular CD31-CD45-MEFSK4+ cardiac fibroblasts were analysed by flow cytometry (≥ 5,000 target cells acquired) to determine surface expression of (B-C) MHCII and (D-E) CD80. n= 4 (mock) and n=3 (Chagas) mice. Error bars represent mean ± SD. (* p≤0.05; *** p<0.001; Mann-Whitney test, two tailed).
Extended Data Fig. 2 MhcII recombination in cardiac fibroblasts occurred in a cell-specific manner.
Detection of Intact allele (310bp), recombined alleles (475 bp) and GAPDH(156 bp) in sorted CD31-CD45-MEFSK4+ Fibroblasts and leukocytes from Tcf21iCre/+MhcIIfl/fl mice treated with vehicle or Tamoxifen. GAPDH was used as loading control.
Extended Data Fig. 3 Tamoxifen treatment of Tcf21iCre/+/ MhcIIflox/flox mice reduces MHCII surface protein expression specifically in cardiac fibroblasts.
Transverse aortic constriction (TAC) surgery was performed on vehicle and Tamoxifen treated Tcf21iCre/+MhcIIfl/fl mice and the left ventricle was harvested after 4 weeks, digested, stained and analysed by flow cytometry. (A) Representative FACS plot showing gating of CD31+CD45-MESFK4- endothelial cells, CD31-CD45+MESFK4- leukocytes and CD31-CD45-MESFK4+ cardiac fibroblasts. (B-C) Representative FACS plots (B) and quantification of mean fluorescence intensity (MFI) (C) of MHC-II expression in endothelial cells (top), leukocytes (middle) and cardiac fibroblasts (bottom) in the hearts of vehicle and tamoxifen treated mice. n=4 mice/group. Error bars represent mean ± SE. (* p<0.05; Mann-Whitney test, two tailed. C: p value=0.0286).
Extended Data Fig. 4 Cardiac fibroblast MHCII expression does not affect CD4+ T cell activation in the mLNs in response to TAC.
Transverse aortic constriction (TAC) surgery was performed on vehicle and Tamoxifen treated Tcf21iCre/+MhcIIfl/fl mice and the mediastinal lymph nodes were harvested after 4 weeks, stained and analysed by flow cytometry for the indicated T cell activation markers. (A) Representative FACS plot showing CD62L and CD44 staining. (B-C) quantification of CD62LlowCD44hi effector T CD4+ T cell numbers (B) and frequency (C) in vehicle and tamoxifen treated TAC mice. n=5 mice (vehicle) and n=6 mice (tamoxifen). Error bars represent mean ± SD. (Mann-Whitney test, two tailed. C: p value=0.0286).
Extended Data Fig. 5 Cardiac fibroblast MHCII expression contributes to cardiomyocyte hypertrophy and to cardiac fibroblast abundance in response to pressure overload.
Transverse aortic constriction (TAC) was performed on vehicle and Tamoxifen treated Tcf21iCre/+MhcIIfl/fl mice and harvested after 4 weeks. Conditional deletion of MhcII on cardiac fibroblasts was induced by administering Tamoxifen via intraperitoneal injections prior to TAC surgery, followed by Tamoxifen citrate chow for 4 weeks. (A) Wheat germ agglutinin (WGA) staining of frozen LV tissue sections was performed and used to calculate (B) mean cardiomyocyte area. Representative images of n=3 hearts (Sham), n=4 (TAC vehicle) and n=7 (TAC TMX). (C) Gross LV mass was acquired and is shown normalized to tibia length. (D-E) LV tissue was digested, stained for CD31 and MESFK4 and analysed by flow cytometry. Representative FACS plot (D) and quantification (E) of vehicle and tamoxifen treated mice hearts (n=4 mice/group). Error bars represent mean ± SE. (* p<0.01; Mann-Whitney test, two tailed: E: p=0286).
Extended Data Fig. 6 Schematic Diagram showing bidirectionality of cardiac fibroblast and Th1 cell interactions.
Cardiac fibroblasts express the costimulatory molecule CD80 and efficiently capture and process extracellular antigens into small peptides that are uploaded into MHC-II molecules. In response to IFNγ stimulation, cardiac fibroblasts express MHCII and present peptide antigens that induce IFNγ + Th1 cell immune responses and promote cardiac remodelling and dysfunction.
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Ngwenyama, N., Kaur, K., Bugg, D. et al. Antigen presentation by cardiac fibroblasts promotes cardiac dysfunction. Nat Cardiovasc Res 1, 761–774 (2022). https://doi.org/10.1038/s44161-022-00116-7
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DOI: https://doi.org/10.1038/s44161-022-00116-7
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