Skip main navigation

T-Cell MyD88 Is a Novel Regulator of Cardiac Fibrosis Through Modulation of T-Cell Activation

Originally published Research. 2023;133:412–429


    Cardiac inflammation in heart failure is characterized by the presence of damage-associated molecular patterns, myeloid cells, and T cells. Cardiac damage-associated molecular patterns provide continuous proinflammatory signals to myeloid cells through TLRs (toll-like receptors) that converge onto the adaptor protein MyD88 (myeloid differentiation response 88). These induce activation into efficient antigen-presenting cells that activate T cells through their TCR (T-cell receptor). T-cell activation results in cardiotropism, cardiac fibroblast transformation, and maladaptive cardiac remodeling. T cells rely on TCR signaling for effector function and survival, and while they express MyD88 and damage-associated molecular pattern receptors, their role in T-cell activation and cardiac inflammation is unknown.


    We performed transverse aortic constriction in mice lacking MyD88 in T cells and analyzed remodeling, systolic function, survival, and T-cell activation. We profiled wild type versus Myd88−/− mouse T cells at the transcript and protein level and performed several functional assays.


    Analysis of single-cell RNA-sequencing data sets revealed that MyD88 is expressed in mouse and human cardiac T cells. MyD88 deletion in T cells resulted in increased levels of cardiac T-cell infiltration and fibrosis in response to transverse aortic constriction. We discovered that TCR-activated Myd88−/− T cells had increased proinflammatory signaling at the transcript and protein level compared with wild type, resulting in increased T-cell effector functions such as adhesion, migration across endothelial cells, and activation of cardiac fibroblast. Mechanistically, we found that MyD88 modulates T-cell activation and survival through TCR-dependent rather than TLR-dependent signaling.


    Our results outline a novel intrinsic role for MyD88 in limiting T-cell activation that is central to tune down cardiac inflammation during cardiac adaptation to stress.


    For Sources of Funding and Disclosures, see page 427.

    Supplemental Material is available at

    Correspondence to: Pilar Alcaide, PhD, Tufts University, 137 Harrison Ave, Boston, MA 02111. Email


    • 1. Smolgovsky S, Ibeh U, Tamayo TP, Alcaide P. Adding insult to injury - inflammation at the heart of cardiac fibrosis.Cell Signal. 2021; 77:109828. doi: 10.1016/j.cellsig.2020.109828CrossrefMedlineGoogle Scholar
    • 2. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377:1119–1131. doi: 10.1056/NEJMoa1707914CrossrefMedlineGoogle Scholar
    • 3. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT; Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-α, in patients with moderate-to-severe heart failure.Circulation. 2003; 107:3133–3140. doi: 10.1161/01.CIR.0000077913.60364.D2LinkGoogle Scholar
    • 4. Yang D, Han Z, Oppenheim JJ. Alarmins and immunity.Immunol Rev. 2017; 280:41–56. doi: 10.1111/imr.12577CrossrefMedlineGoogle Scholar
    • 5. Mann DL. Innate immunity and the failing heart.Circ Res. 2015; 116:1254–1268. doi: 10.1161/CIRCRESAHA.116.302317LinkGoogle Scholar
    • 6. Zhang L, Liu M, Jiang H, Yu Y, Yu P, Tong R, Wu J, Zhang S, Yao K, Zou Y, et al. Extracellular high-mobility group box 1 mediates pressure overload-induced cardiac hypertrophy and heart failure.J Cell Mol Med. 2016; 20:459–470. doi: 10.1111/jcmm.12743CrossrefMedlineGoogle Scholar
    • 7. Suetomi T, Willeford A, Brand CS, Cho Y, Ross RS, Miyamoto S, Brown JH. Inflammation and NLRP3 inflammasome activation initiated in response to pressure overload by CaMKIIδ signaling in cardiomyocytes are essential for adverse cardiac remodeling.Circulation. 2018; 138:2530–2544. doi: 10.1161/CIRCULATIONAHA.118.034621LinkGoogle Scholar
    • 8. Cohen P. The TLR and IL-1 signalling network at a glance.J Cell Sci. 2014; 127:2383–2390. doi: 10.1242/jcs.149831CrossrefMedlineGoogle Scholar
    • 9. Deguine J, Barton GM. MyD88: a central player in innate immune signaling.F1000Prime Rep. 2014; 6:97. doi: 10.12703/P6-97CrossrefMedlineGoogle Scholar
    • 10. Nevers T, Salvador AM, Grodecki-Pena A, Knapp A, Velázquez F, Aronovitz M, Kapur NK, Karas RH, Blanton RM, Alcaide P. Left ventricular T-cell recruitment contributes to the pathogenesis of heart failure.Circ Heart Fail. 2015; 8:776–787. doi: 10.1161/CIRCHEARTFAILURE.115.002225LinkGoogle Scholar
    • 11. Laroumanie F, Douin-Echinard V, Pozzo J, Lairez O, Tortosa F, Vinel C, Delage C, Calise D, Dutaur M, Parini A, et al. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload.Circulation. 2014; 129:2111–2124. doi: 10.1161/CIRCULATIONAHA.113.007101LinkGoogle Scholar
    • 12. Nevers T, Salvador AM, Velazquez F, Ngwenyama N, Carrillo-Salinas FJ, Aronovitz M, Blanton RM, Alcaide P. Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure.J Exp Med. 2017; 214:3311–3329. doi: 10.1084/jem.20161791CrossrefMedlineGoogle Scholar
    • 13. Ngwenyama N, Kirabo A, Aronovitz M, Velázquez F, Carrillo-Salinas F, Salvador AM, Nevers T, Amarnath V, Tai A, Blanton RM, et al. Isolevuglandin-modified cardiac proteins drive CD4+ T cell activation in the heart and promote cardiac dysfunction.Circulation. 2021; 143:1242–1255. doi: 10.1161/CIRCULATIONAHA.120.051889LinkGoogle Scholar
    • 14. Ngwenyama N, Kaur K, Bugg D, Theall B, Aronovitz M, Berland R, Panagiotidou S, Genco C, Perrin MA, Davis J, et al. Antigen presentation by cardiac fibroblasts promotes cardiac dysfunction.Nat Cardiovasc Res. 2022; 1:761–774. doi: 10.1038/s44161-022-00116-7CrossrefMedlineGoogle Scholar
    • 15. Ha T, Hua F, Li Y, Ma J, Gao X, Kelley J, Zhao A, Haddad GE, Williams DL, Browder IW, et al. Blockade of MyD88 attenuates cardiac hypertrophy and decreases cardiac myocyte apoptosis in pressure overload-induced cardiac hypertrophy in vivo.Am J Physiol Heart Circ Physiol. 2006; 290:H985–H994. doi: 10.1152/ajpheart.00720.2005CrossrefMedlineGoogle Scholar
    • 16. Iwasaki A, Medzhitov R. Toll-like receptor control of the adaptive immune responses.Nat Immunol. 2004; 5:987–995. doi: 10.1038/ni1112CrossrefMedlineGoogle Scholar
    • 17. Reynolds JM, Dong C. Toll-like receptor regulation of effector T lymphocyte function.Trends Immunol. 2013; 34:511–519. doi: 10.1016/ Scholar
    • 18. Bayer AL, Alcaide P. MyD88: at the heart of inflammatory signaling and cardiovascular disease.J Mol Cell Cardiol. 2021; 161:75–85. doi: 10.1016/j.yjmcc.2021.08.001CrossrefMedlineGoogle Scholar
    • 19. Mardiney M, Malech HL. Enhanced engraftment of hematopoietic progenitor cells in mice treated with granulocyte colony-stimulating factor before low-dose irradiation: implications for gene therapy.Blood. 1996; 87:4049–4056.MedlineGoogle Scholar
    • 20. Mombaerts P, Clarke AR, Rudnicki MA, Iacomini J, Itohara S, Lafaille JJ, Wang L, Ichikawa Y, Jaenisch R, Hooper ML. Mutations in T-cell antigen receptor genes α and β block thymocyte development at different stages.Nature. 1992; 360:225–231. doi: 10.1038/360225a0CrossrefMedlineGoogle Scholar
    • 21. Adachi O, Kawai T, Takeda K, Matsumoto M, Tsutsui H, Sakagami M, Nakanishi K, Akira S. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.Immunity. 1998; 9:143–150. doi: 10.1016/s1074-7613(00)80596-8CrossrefMedlineGoogle Scholar
    • 22. Hou B, Reizis B, DeFranco AL. Toll-like receptor-mediated dendritic cell-dependent and -independent stimulation of innate and adaptive immunity.Immunity. 2008; 29:272–282. doi: 10.1016/j.immuni.2008.05.016CrossrefMedlineGoogle Scholar
    • 23. Lee PP, Fitzpatrick DR, Beard C, Jessup HK, Lehar S, Makar KW, Pérez-Melgosa M, Sweetser MT, Schlissel MS, Nguyen S, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.Immunity. 2001; 15:763–774. doi: 10.1016/s1074-7613(01)00227-8CrossrefMedlineGoogle Scholar
    • 24. Martini E, Kunderfranco P, Peano C, Carullo P, Cremonesi M, Schorn T, Carriero R, Termanini A, Colombo FS, Jachetti E, et al. Single-cell sequencing of mouse heart immune infiltrate in pressure overload–driven heart failure reveals extent of immune activation.Circulation. 2019; 140:2089–2107. doi: 10.1161/CIRCULATIONAHA.119.041694LinkGoogle Scholar
    • 25. Amrute JM, Luo X, Penna V, Bredemeyer A, Yamawaki T, Heo GS, Shi S, Koenig A, Yang S, Kadyrov F, et al. Targeting the immune-fibrosis axis in myocardial infarction and heart failure.bioRivx. Preprint posted online October 21, 2022. doi: 10.1101/2022.10.17.512579CrossrefGoogle Scholar
    • 26. Ngwenyama N, Salvador AM, Velázquez F, Nevers T, Levy A, Aronovitz M, Luster AD, Huggins GS, Alcaide P. CXCR3 regulates CD4+ T cell cardiotropism in pressure overload–induced cardiac dysfunction.JCI Insight. 2019; 4:e125527. doi: 10.1172/jci.insight.125527CrossrefMedlineGoogle Scholar
    • 27. Piali L, Weber C, LaRosa G, Mackay CR, Springer TA, Clark-Lewis I, Moser B. The chemokine receptor CXCR3 mediates rapid and shear-resistant adhesion-induction of effector T lymphocytes by the chemokines IP10 and Mig.Eur J Immunol. 1998; 28:961–972. doi: 10.1002/(SICI)1521-4141(199803)28:03<961::AID-IMMU961>3.0.CO;2-4CrossrefMedlineGoogle Scholar
    • 28. Yi J, Balagopalan L, Nguyen T, McIntire KM, Samelson LE. TCR microclusters form spatially segregated domains and sequentially assemble in calcium-dependent kinetic steps.Nat Commun. 2019; 10:277. doi: 10.1038/s41467-018-08064-2CrossrefMedlineGoogle Scholar
    • 29. Schenten D, Nish SA, Yu S, Yan X, Lee HK, Brodsky I, Pasman L, Yordy B, Wunderlich FT, Brüning JC, et al. Signaling through the adaptor molecule MyD88 in CD4+ T cells is required to overcome suppression by regulatory T cells.Immunity. 2014; 40:78–90. doi: 10.1016/j.immuni.2013.10.023CrossrefMedlineGoogle Scholar
    • 30. Cataisson C, Salcedo R, Michalowski AM, Klosterman M, Naik S, Li L, Pan MJ, Sweet A, Chen JQ, Kostecka LG, et al. T-cell deletion of MyD88 connects IL17 and IκBζ to RAS oncogenesis.Mol Cancer Res. 2019; 17:1759–1773. doi: 10.1158/1541-7786.MCR-19-0227CrossrefMedlineGoogle Scholar
    • 31. Borges CM, Reichenbach DK, Kim BS, Misra A, Blazar BR, Turka LA. T regulatory cell expressed Myd88 is critical for prolongation of allograft survival.Transpl Int Off J Eur Soc Organ Transplant. 2016; 29:930–940. doi: 10.1111/tri.12788CrossrefMedlineGoogle Scholar
    • 32. Johansen KH, Golec DP, Thomsen JH, Schwartzberg PL, Okkenhaug K. PI3K in T cell adhesion and trafficking.Front Immunol. 2021; 12:708908. doi: 10.3389/fimmu.2021.708908CrossrefMedlineGoogle Scholar
    • 33. Groom JR, Luster AD. CXCR3 in T cell function.Exp Cell Res. 2011; 317:620–631. doi: 10.1016/j.yexcr.2010.12.017CrossrefMedlineGoogle Scholar
    • 34. Wojno EDT, Hunter CA, Stumhofer JS. The immunobiology of the interleukin-12 family: room for discovery.Immunity. 2019; 50:851–870. doi: 10.1016/j.immuni.2019.03.011CrossrefMedlineGoogle Scholar
    • 35. Funayama A, Shishido T, Netsu S, Narumi T, Kadowaki S, Takahashi H, Miyamoto T, Watanabe T, Woo C-H, Abe J, et al. Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure.Cardiovasc Res. 2013; 99:657–664. doi: 10.1093/cvr/cvt128CrossrefMedlineGoogle Scholar
    • 36. Lin H, Shen L, Zhang X, Xie J, Hao H, Zhang Y, Chen Z, Yamamoto H, Liao W, Bin J, et al. HMGB1-RAGE axis makes no contribution to cardiac remodeling induced by pressure-overload.PLoS One. 2016; 11:e0158514. doi: 10.1371/journal.pone.0158514CrossrefMedlineGoogle Scholar
    • 37. Jin B, Sun T, Yu XH, Yang YX, Yeo AET. The effects of TLR activation on T-cell development and differentiation.Clin Dev Immunol. 2012; 2012:1–32. doi: 10.1155/2012/836485CrossrefGoogle Scholar
    • 38. Rahman AH, Taylor DK, Turka LA. The contribution of direct TLR signaling to T cell responses.Immunol Res. 2009; 45:25–36. doi: 10.1007/s12026-009-8113-xCrossrefMedlineGoogle Scholar
    • 39. Turner NA. Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs).J Mol Cell Cardiol. 2016; 94:189–200. doi: 10.1016/j.yjmcc.2015.11.002CrossrefMedlineGoogle Scholar
    • 40. Theall B, Alcaide P. The heart under pressure: immune cells in fibrotic remodeling.Curr Opin Physiol. 2022; 25:100484. doi: 10.1016/j.cophys.2022.100484CrossrefMedlineGoogle Scholar
    • 41. Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, Lin SCJ, Aronow BJ, Tallquist MD, et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart.Nat Commun. 2016; 7:12260. doi: 10.1038/ncomms12260CrossrefMedlineGoogle Scholar
    • 42. Reichardt IM, Robeson KZ, Regnier M, Davis J. Controlling cardiac fibrosis through fibroblast state space modulation.Cell Signal. 2021; 79:109888. doi: 10.1016/j.cellsig.2020.109888CrossrefMedlineGoogle Scholar
    • 43. Ivey MJ, Kuwabara JT, Pai JT, Moore RE, Sun Z, Tallquist MD. Resident fibroblast expansion during cardiac growth and remodeling.J Mol Cell Cardiol. 2018; 114:161–174. doi: 10.1016/j.yjmcc.2017.11.012CrossrefMedlineGoogle Scholar
    • 44. Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review.J Cell Physiol. 2019; 234:8509–8521. doi: 10.1002/jcp.27782CrossrefMedlineGoogle Scholar
    • 45. Axelrod ML, Meijers WC, Screever EM, Qin J, Carroll MG, Sun X, Tannous E, Zhang Y, Sugiura A, Taylor BC, et al. T cells specific for α-myosin drive immunotherapy-related myocarditis.Nature. 2022; 611:818–826. doi: 10.1038/s41586-022-05432-3CrossrefMedlineGoogle Scholar
    • 46. Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GGL, Van Tassell BW, Robati R, Roach LM, Arena RA, Roberts CS, Varma A, et al; VCU-ART Investigators. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] pilot study).Am J Cardiol. 2010; 105:1371–1377.e1. doi: 10.1016/j.amjcard.2009.12.059CrossrefMedlineGoogle Scholar
    • 47. Richards DA, Aronovitz MJ, Calamaras TD, Tam K, Martin GL, Liu P, Bowditch HK, Zhang P, Huggins GS, Blanton RM. Distinct phenotypes induced by three degrees of transverse aortic constriction in mice.Sci Rep. 2019; 9:5844. doi: 10.1038/s41598-019-42209-7CrossrefMedlineGoogle Scholar
    • 48. Carrillo-Salinas FJ, Anastasiou M, Ngwenyama N, Kaur K, Tai A, Smolgovsky SA, Jetton D, Aronovitz M, Alcaide P. Gut dysbiosis induced by cardiac pressure overload enhances adverse cardiac remodeling in a T cell-dependent manner.Gut Microbes. 2020; 12:1–20. doi: 10.1080/19490976.2020.1823801CrossrefMedlineGoogle Scholar
    • 49. Kaur K, Velázquez FE, Anastasiou M, Ngwenyama N, Smolgovsky S, Aronovitz M, Alcaide P. Sialomucin CD43 plays a deleterious role in the development of experimental heart failure induced by pressure overload by modulating cardiac inflammation and fibrosis.Front Physiol. 2021; 12:780854. doi: 10.3389/fphys.2021.780854CrossrefMedlineGoogle Scholar
    • 50. Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ, Wilk AJ, Darby C, Zager M, et al. Integrated analysis of multimodal single-cell data.Cell. 2021; 184:3573–3587.e29. doi: 10.1016/j.cell.2021.04.048CrossrefMedlineGoogle Scholar
    • 51. Anastasiou M, Newton GA, Kaur K, Carrillo-Salinas FJ, Smolgovsky SA, Bayer AL, Ilyukha V, Sharma S, Poltorak A, Luscinskas FW, et al. Endothelial STING controls Tcell transmigration in an IFN-I dependent manner.JCI Insight. 2021; 6:e149346. doi: 10.1172/jci.insight.149346CrossrefMedlineGoogle Scholar


    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.