Original Article
  

Response of Human T Cells to Tetanus Neurotoxin HCC Sub-Domain: T Cell Cytokine Production and Activation Marker Induced by HCC

Abstract

Tetanus is caused by the tetanus neurotoxin (TeNT), a 150 kDa single polypeptide molecule which is cleaved into active two-chain molecules composed of a 50 kDa N-terminal light (L) and a 100 kDa C-terminal heavy (H) chains. Fragment C is further subdivided into two subdomains: the proximal HCN  subdomain and the extreme carboxy subdomain, HCC. HCC is considered as an immunodominant part of TeNT and is responsible for TeNT binding activity to neurons.In the present study, we investigated the ability of recombinant HCC(r HCC) to induce T cell activation. Our results showed that recombinant HCC has a stimulatory effect on IFN-γ secretion by T cells after 48h co-incubation in the presence of anti-TLR-2 Ab. Also, Hcc can induce the expression of CD69 on T cells.Our finding indicated that stimulatory effects of HCC on T cells are TLR-2 independent and anti-TLR-2 inhibitory antibody fails to neutralize HCC stimulatory effects on T cells.Furthermore, HCC  is critical for immunogenic activity of TeNT and is able to induce T cells through TLR-2 independent pathway.

1. Cook TM, Protheroe RT, Handel JM. Tetanus: a review of the literature. Br J Anaesth 2001; 87(3):477-87.

2. Rawlings ND, Barrett AJ. [13] Evolutionary families of metallopeptidases. Methods Enzymol 1995; 248:183-228.

3. Montecucco C, Schiavo G. Mechanism of action of tetanus and botulinum neurotoxins. Mol Microbiol 1994;13(1):1-8.

4. Schiavo G, Papini E, Genna G, Montecucco C. An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect Immun 1990;58(12):4136-41.

5. Schiavo GG, Benfenati F, Poulain B, Rossetto O, de Laureto PP, DasGupta BR, et al. Tetanus and botulinum- B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin. Nature 1992;359(6398):832-5.

6. Herreros J, Lalli G, Schiavo G. C-terminal half of tetanus toxin fragment C is sufficient for neuronal binding and interaction with a putative protein receptor. Biochem J 2000; 347:199-204.

7. Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev 2000; 80(2):717-66.

8. Diethelm-Okita BM, Okita DK, Banaszak L, Conti-Fine BM. Universal epitopes for human CD4+ cells on tetanus and diphtheria toxins. J Infect Dis 2000; 181(3):1001-9.

9. Tymciu S, Durieux-Alexandrenne C, Wijkhuisen A, Créminon C, Frobert Y, Grassi J, et al. Enhancement of antibody responses in DNA vaccination using a vector encoding a universal T-helper cell epitope. DNA Cell Biol 2004; 23(6):395-402.

10. Parronchi P, Macchia D, Piccinni M-P, Biswas P, Simonelli C, Maggi E, et al. Allergen-and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A 1991; 88(10):4538-42.

11. Kumar H, Kawai T, Akira S. Toll-like receptors and innate immunity. Biochem Biophys Res Commun 2009;388(4):621-5.

12. Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 2011; 34(5):637-50.

13. Yousefi M, Khosravi-Eghbal R, Hemmati A, Shokri F.Production and Characterization of Recombinant Light Chain and Carboxyterminal Heavy Chain Fragments of Tetanus Toxin. Avicenna J Med Biotechnol 2013;5(4):220-6.

14. Adams PW, Mitchell Opremcak E, Orosz CG. Limiting dilution analysis of human, tetanus-reactive helper T lymphocytes: a rapid method for the enumeration of helper T lymphocytes with specificity for soluble antigens. J Immunol Methods 1991; 142(2):231-41.

15. Yamashita I, Nagata T, Tada T, Nakayama T. CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection. Int Immunol 1993; 5(9):1139-50.

16. Schwab SR, Cyster JG. Finding a way out: lymphocyte egress from lymphoid organs. Nat Immunol 2007;8(12):1295-301.

17. Geha RS, Schneeberger E, Rosen FS, Merler E.Interaction of human thymus-derived and non-thymus- derived lymphocytes in vitro. Induction of proliferation and antibody synthesis in B lymphocytes by a soluble factor released from antigen-stimulated T lymphocytes.. J Exp Med 1973; 138(5):1230-47.

18. Kozbor D, Trinchieri G, Monos DS, Isobe M, Russo G, Haney J, et al. Human TCR-gamma+/delta+, CD8+ T lymphocytes recognize tetanus toxoid in an MHC- restricted fashion. J Exp Med 1989; 169(5):1847-51.

19. Yousefi M, Tahmasebi F, Younesi V, Razavi A, Khoshnoodi J, Bayat AA, et al. Characterization of neutralizing monoclonal antibodies directed against tetanus toxin fragment C. J Immunotoxicol 2013;11(1):28-34.

20. Asgarian‐Omran H, Amirzargar AA, Zeerleder S, Mahdavi M, Mierlo G, Solati S, et al. Interaction of Bordetella pertussis filamentous hemagglutinin with human TLR2: identification of the TLR2‐binding domain. APMIS 2015; 123(2):156-62.

21. Komai-Koma M, Jones L, Ogg GS, Xu D, Liew FY.

TLR2 is expressed on activated T cells as a costimulatory receptor. Proceedings of the National Academy of Sciences of the United States of America 2004;101(9):3029-34.

22. Zanin-Zhorov A, Nussbaum G, Franitza S, Cohen IR, Lider O. T cells respond to heat shock protein 60 via TLR2: activation of adhesion and inhibition of chemokine receptors. The FASEB J 2003; 17(11):1567-9.

23. Poltorak A, He X, Smirnova I, Liu M-Y, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282(5396):2085-8.

24. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nature immunol 2001; 2(8):675-80.

25. Ohashi K, Burkart V, Flohé S, Kolb H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 2000;164(2):558-61.

Files
IssueVol 14, No 5 (2015) QRcode
SectionOriginal Article(s)
Keywords
HCC subdomain TeNT T cell TLR-2 IFN-γ
Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Ghafari-Khamene M, Torabi-Goudarzi S, Hosseini M, Haji-Fatahaliha M, Sadreddini S, Seyfi-Najmi M, Majidi J, Yousefi M. Response of Human T Cells to Tetanus Neurotoxin HCC Sub-Domain: T Cell Cytokine Production and Activation Marker Induced by HCC. Iran J Allergy Asthma Immunol. 2015;14(5):519-525.