Skip to main content

Advertisement

SpringerLink
Log in

Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Regulatory T cells (Tregs) have been reported to play a pivotal role in the vascular remodeling of pulmonary arterial hypertension (PAH). Recent studies have revealed that Tregs are heterogeneous and can be characterized by three phenotypically and functionally different subsets. In this study, we investigated the roles of Treg subsets in the pathogenesis of PAH in eight patients with PAH and 14 healthy controls. Tregs and their subsets in peripheral blood samples were analyzed by flow cytometry. Treg subsets were defined as CD4+CD45RA+FoxP3low resting Tregs (rTregs), CD4+CD45RA−FoxP3high activated Tregs (aTregs), and CD4+CD45RA−FoxP3low non-suppressive Tregs (non-Tregs). The proportion of Tregs among CD4+ T cells was significantly higher in PAH patients than in controls (6.54 ± 1.10 vs. 3.81 ± 0.28 %, p < 0.05). Of the three subsets, the proportion of non-Tregs was significantly elevated in PAH patients compared with controls (4.06 ± 0.40 vs. 2.79 ± 0.14 %, p < 0.01), whereas those of rTregs and aTregs were not different between the two groups. Moreover, the expression levels of cytotoxic T lymphocyte antigen 4, a functional cell surface molecule, in aTregs (p < 0.05) and non-Tregs (p < 0.05) were significantly higher in PAH patients compared with controls. These results suggested the non-Treg subset was expanded and functionally activated in peripheral lymphocytes obtained from IPAH patients. We hypothesize that immunoreactions involving the specific activation of the non-Treg subset might play a role in the vascular remodeling of PAH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF (2005) Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J 26:1110–1118

    Article  CAS  PubMed  Google Scholar 

  2. Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, Dartevelle P, Simonneau G, Adnot S, Eddahibi S (2007) Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 176:1041–1047

    Article  CAS  PubMed  Google Scholar 

  3. Hall S, Brogan P, Haworth SG, Klein N (2009) Contribution of inflammation to the pathology of idiopathic pulmonary arterial hypertension in children. Thorax 64:778–783

    Article  CAS  PubMed  Google Scholar 

  4. Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW (2010) Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122:920–927

    Article  CAS  PubMed  Google Scholar 

  5. Sugiura T, Yamanaka S, Takeuchi H, Morimoto N, Kamioka M, Matsumura Y (2014) Autoimmunity and pulmonary hypertension in patients with Graves’ disease. Heart Vessels. doi:10.1007/s00380-014-0518-3

    PubMed Central  Google Scholar 

  6. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  CAS  PubMed  Google Scholar 

  7. Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500

    Article  CAS  PubMed  Google Scholar 

  8. Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L, Patterson AJ, Agrawal R, Rabinovitch M, Ambler K, Long CS, Voelkel NF, Nicolls MR (2011) Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 109:867–879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ulrich S, Nicolls MR, Taraseviciene L, Speich R, Voelkel N (2008) Increased regulatory and decreased CD8+ cytotoxic T cells in the blood of patients with idiopathic pulmonary arterial hypertension. Respiration 75:272–280

    Article  CAS  PubMed  Google Scholar 

  10. Austin ED, Rock MT, Mosse CA, Vnencak-Jones CL, Yoder SM, Robbins IM, Loyd JE, Meyrick BO (2010) T lymphocyte subset abnormalities in the blood and lung in pulmonary arterial hypertension. Respir Med 104:454–462

    Article  CAS  PubMed  Google Scholar 

  11. Huertas A, Tu L, Gambaryan N, Girerd B, Perros F, Montani D, Fabre D, Fadel E, Eddahibi S, Cohen-Kaminsky S, Guignabert C, Humbert M (2012) Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur Respir J 40:895–904

    Article  CAS  PubMed  Google Scholar 

  12. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, Mathian A, Nakahata T, Yamaguchi T, Nomura T, Ono M, Amoura Z, Gorochov G, Sakaguchi S (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911

    Article  CAS  PubMed  Google Scholar 

  13. Buckner JH (2010) Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10:849–859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yoshioka N, Suto A, Abe R, Saito N, Murata J, Hayashi-Ujiie I, Hoshina D, Fujita Y, Shimizu H (2013) Disturbed balance in three subpopulations of CD4(+)Foxp3(+) regulatory T cells in Stevens-Johnson syndrome and toxic epidermal necrolysis patients. Clin Immunol 148:89–91

    Article  CAS  PubMed  Google Scholar 

  15. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Tran DQ (2013) In vitro suppression assay for functional assessment of human regulatory T cells. Methods Mol Biol 979:199–212

    Article  CAS  PubMed  Google Scholar 

  17. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA 3rd, Soubrier F, Trembath RC, Chung WK (2009) Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 54:S32–S42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Morrell NW (2006) Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 3:680–686

    Article  CAS  PubMed  Google Scholar 

  19. Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jais X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, Sitbon O, O’Callaghan DS, Simonneau G, Soubrier F, Humbert M (2010) Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 181:851–861

    Article  CAS  PubMed  Google Scholar 

  20. Bertolino P, Deckers M, Lebrin F, ten Dijke P (2005) Transforming growth factor-beta signal transduction in angiogenesis and vascular disorders. Chest 128:585S–590S

    Article  CAS  PubMed  Google Scholar 

  21. Zhang YE (2009) Non-Smad pathways in TGF-beta signaling. Cell Res 19:128–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Long L, Crosby A, Yang X, Southwood M, Upton PD, Kim DK, Morrell NW (2009) Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat models of pulmonary hypertension: potential for activin receptor-like kinase-5 inhibition in prevention and progression of disease. Circulation 119:566–576

    Article  CAS  PubMed  Google Scholar 

  23. Pardali E, Ten Dijke P (2012) TGFbeta signaling and cardiovascular diseases. Int J Biol Sci 8:195–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC (2001) Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 104:790–795

    Article  CAS  PubMed  Google Scholar 

  25. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW (2002) Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672–1678

    Article  CAS  PubMed  Google Scholar 

  26. Takahashi H, Goto N, Kojima Y, Tsuda Y, Morio Y, Muramatsu M, Fukuchi Y (2006) Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 290:L450–L458

    Article  CAS  PubMed  Google Scholar 

  27. Morty RE, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri FM, Peters DM, Dumitrascu R, Seeger W, Knaus P, Schermuly RT, Eickelberg O (2007) Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 27:1072–1078

    Article  CAS  PubMed  Google Scholar 

  28. Davies RJ, Holmes AM, Deighton J, Long L, Yang X, Barker L, Walker C, Budd DC, Upton PD, Morrell NW (2012) BMP type II receptor deficiency confers resistance to growth inhibition by TGF-beta in pulmonary artery smooth muscle cells: role of proinflammatory cytokines. Am J Physiol Lung Cell Mol Physiol 302:L604–L615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guo Y, Su L, Li Y, Guo N, Xie L, Zhang D, Zhang X, Li H, Zhang G, Wang Y, Liu C (2014) The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats. Heart Vessels 29:520–531

    Article  PubMed  Google Scholar 

  30. Ouyang W, Beckett O, Ma Q, Li MO (2010) Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 32:642–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Yoshiharu Sada, Yoshihiro Dohi, Sayuri Uga, Akifumi Higashi, Hiroki Kinoshita & Yasuki Kihara

Authors
  1. Yoshiharu Sada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshihiro Dohi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sayuri Uga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akifumi Higashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroki Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuki Kihara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshihiro Dohi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sada, Y., Dohi, Y., Uga, S. et al. Non-suppressive regulatory T cell subset expansion in pulmonary arterial hypertension. Heart Vessels 31, 1319–1326 (2016). https://doi.org/10.1007/s00380-015-0727-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-015-0727-4

Keywords

Search

Navigation