Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease

Cellular & Molecular Immunology volume 15, pages 1091–1094 (2018)Cite this article

Subjects

Mendelian susceptibility to mycobacterial disease (MSMD) is an inherited predisposition to infections by Bacille-Calmette Guérin (BCG) vaccine or by environmental mycobacteria. The etiology of MSMD has been associated with up to nineteen different genetic mutations in interferon (IFN)-γ-related genes.1 Although mycobacteria susceptibility-associated genetic mutations are rare in the population, their diagnosis is crucial for an efficient and timely treatment. Kong et al.2 have recently described an autosomal recessive deficiency in the signal peptidase-like 2 A (SPPL2-a) as a new genetic etiology for MSMD in three patients that had suffered BCG dissemination disease.

SPPL2-a encodes for a transmembrane protease required for the cleavage of the N-terminal fragment (NTF) of a transmembrane glycoprotein (CD74) in the endosome. CD74 binds to the major histocompatibility complex (MHC) class II in the endoplasmic reticulum (Fig. 1).6 Upon the cleavage of CD74, proteolytic degradation takes place and the intracellular domain of the NTF CD74 is degraded. Importantly, Casanova and colleagues showed that an SPPL2-a deficiency causes the accumulation of CD74 in B cells and monocytes from patients. This phenotype was reproduced by the treatment of leucocytes derived from healthy donors with SPPL2a inhibitors, also triggered the accumulation of CD74 in mainly HLA Class II+ APCs, including B cells and DCs.2 As SPPL2a is required for B cell development,7 authors evaluated whether the B cell response was altered in SPPL2a-deficient patients.2 Importantly, no significant B cell deficiency was evidenced in any of these patients, as compared to healthy controls. In this latter study, two out of three patients were twins, which when vaccinated with BCG at birth displayed inflammation at axillary lymph nodes.2 The remaining patient was vaccinated at 2 months of age and presented a left axillary lymphadenopathy.2 It is worth to mention that the majority of the worldwide population is currently vaccinated with the BCG to prevent from Tuberculosis8 and that several recombinant BCGs are under development to prevent from viral infections with promising results.9,10,11

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Rosain J., et al. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol Cell Biol. 2018 Sep 28 https://doi.org/10.6084/m9.figshare.hgv.1920.

  2. Kong, X. F. et al. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat. Immunol. 19, 973–985 (2018).

    Article  CAS  Google Scholar 

  3. Bustamante, J., Boisson-Dupuis, S., Abel, L. & Casanova, J. L. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin. Immunol. 26, 454–470 (2014).

    Article  CAS  Google Scholar 

  4. van de Vosse, E. & van Dissel, J. T. IFN-gammaR1 defects: mutation update and description of the IFNGR1 variation database. Hum. Mutat. 38, 1286–1296 (2017).

    Article  Google Scholar 

  5. Taniguchi, T., Ogasawara, K., Takaoka, A. & Tanaka, N. IRF family of transcription factors as regulators of host defense. Annu. Rev. Immunol. 19, 623–655 (2001).

    Article  CAS  Google Scholar 

  6. Schroder, B. The multifaceted roles of the invariant chain CD74--more than just a chaperone. Biochim. Biophys. Acta 1863, 1269–1281 (2016).

    Article  Google Scholar 

  7. Beisner, D. R. et al. The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain. J. Exp. Med. 210, 23–30 (2013).

    Article  CAS  Google Scholar 

  8. Rey-Jurado, E. et al. Assessing the importance of domestic vaccine manufacturing centers: an overview of immunization programs, vaccine manufacture, and distribution. Front. Immunol. 9, 26 (2018).

    Article  Google Scholar 

  9. Céspedes P. C., et al. A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice. Vaccine. 35, 757–766 (2017).

  10. Cautivo, K. M. et al. Efficient lung recruitment of respiratory syncytial virus-specific Th1 cells induced by recombinant bacillus Calmette-Guerin promotes virus clearance and protects from infection. J. Immunol. 185, 7633–7645 (2010).

    Article  CAS  Google Scholar 

  11. Mahant A., et al. Preclinical development of BCG.HIVA2auxo.int, harboring an integrative expression vector, for a HIV-TB pediatric vaccine. Enhancement of stability and specific HIV-1 T-cell immunity. Hum Vaccin Immunother. ​13, 1798-1810 (2017).

  12. Salem, S. et al. Functional characterization of the human dendritic cell immunodeficiency associated with the IRF8(K108E) mutation. Blood 124, 1894–1904 (2014).

    Article  CAS  Google Scholar 

  13. Doulatov, S. et al. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat. Immunol. 11, 585–593 (2010).

    Article  CAS  Google Scholar 

  14. Ishikawa, F. et al. The developmental program of human dendritic cells is operated independently of conventional myeloid and lymphoid pathways. Blood 110, 3591–3660 (2007).

    Article  CAS  Google Scholar 

  15. Granot, T. et al. Dendritic cells display subset and tissue-specific maturation dynamics over human life. Immunity 46, 504–515 (2017).

    Article  CAS  Google Scholar 

  16. Dirix, V. et al. Blood tolerogenic monocytes and low proportions of dendritic cell subpopulations are hallmarks of human tuberculosis. J. Leukoc. Biol. 103, 945–954 (2018).

    Article  CAS  Google Scholar 

  17. Alodayani, A. N. et al. Mendelian susceptibility to mycobacterial disease caused by a novel founder IL12B mutation in Saudi Arabia. J. Clin. Immunol. 38, 278–282 (2018).

    Article  Google Scholar 

  18. Prando, C. et al. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Med. (Baltim.) 92, 109–122 (2013).

    Article  CAS  Google Scholar 

  19. Lee, W., Kim, H. S., Baek, S. Y. & Lee, G. R. Transcription factor IRF8 controls Th1-like regulatory T-cell function. Cell. Mol. Immunol. 13, 785–794 (2016).

    Article  CAS  Google Scholar 

  20. Nakanishi, Y., Lu, B., Gerard, C. & Iwasaki, A. CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462, 510–513 (2009).

    Article  CAS  Google Scholar 

  21. Liao, F. et al. CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha. J. Immunol. 162, 186–194 (1999).

    CAS  PubMed  Google Scholar 

  22. Vilaplana, C. et al. To achieve an earlier IFN-gamma response is not sufficient to control Mycobacterium tuberculosis infection in mice. PLoS ONE 9, e100830 (2014).

    Article  Google Scholar 

  23. Silva, D. et al. TNF-alpha blockade impairs in vitro tuberculous granuloma formation and down modulate Th1, Th17 and Treg cytokines. PLoS ONE 13, e0194430 (2018).

    Article  Google Scholar 

  24. Rocca, S. et al. Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis. PLoS ONE 8, e62751 (2013).

    Article  CAS  Google Scholar 

  25. van Crevel, R., Ottenhoff, T. H. & van der Meer, J. W. Innate immunity to Mycobacterium tuberculosis. Clin. Microbiol. Rev. 15, 294–309 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by COMISIÓN NACIONAL DE INVESTIGACIÓN CIENTÍFICA Y TECNOLÓGICA (CONICYT) FONDECYT grants N° 1150862 and 3160249, The Millennium Institute on Immunology and Immunotherapy (P09/016-F), COPEC-UC Grant “Concurso Nacional de Proyectos de I + D aplicada en el ámbito de los Recursos Naturales” n°2016.R.772. We also acknowledge Trinidad Cellis Donner for the support with figure design.

Author information

Authors and Affiliations

  1. Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile

    Emma Rey-Jurado, Magdalena S. Pizarro-Ortega & Alexis M. Kalergis

  2. Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, 8330644, Chile

    Alexis M. Kalergis

Authors
  1. Emma Rey-Jurado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Magdalena S. Pizarro-Ortega
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexis M. Kalergis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexis M. Kalergis.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rey-Jurado, E., Pizarro-Ortega, M.S. & Kalergis, A.M. Insights on the crosstalk between dendritic cells and helper T cells in novel genetic etiology for mendelian susceptible mycobacterial disease. Cell Mol Immunol 15, 1091–1094 (2018). https://doi.org/10.1038/s41423-018-0177-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-018-0177-x

Keywords

Search

Advanced search

Quick links