ML1419c peptide immunization induces Mycobacterium leprae-specific HLA-A*0201-restricted CTL in vivo with potential to kill live mycobacteria.

Abstract

MHC class I-restricted CD8(+) T cells play an important role in protective immunity against mycobacteria. Previously, we showed that p113-121, derived from Mycobacterium leprae protein ML1419c, induced significant IFN-γ production by CD8(+) T cells in 90% of paucibacillary leprosy patients and in 80% of multibacillary patients' contacts, demonstrating induction of M. leprae-specific CD8(+) T cell immunity. In this work, we studied the in vivo role and functional profile of ML1419c p113-121-induced T cells in HLA-A*0201 transgenic mice. Immunization with 9mer or 30mer covering the p113-121 sequence combined with TLR9 agonist CpG induced HLA-A*0201-restricted, M. leprae-specific CD8(+) T cells as visualized by p113-121/HLA-A*0201 tetramers. Most CD8(+) T cells produced IFN-γ, but distinct IFN-γ(+)/TNF-α(+) populations were detected simultaneously with significant secretion of CXCL10/IFN-γ-induced protein 10, CXCL9/MIG, and VEGF. Strikingly, peptide immunization also induced high ML1419c-specific IgG levels, strongly suggesting that peptide-specific CD8(+) T cells provide help to B cells in vivo, as CD4(+) T cells were undetectable. An additional important characteristic of p113-121-specific CD8(+) T cells was their capacity for in vivo killing of p113-121-labeled, HLA-A*0201(+) splenocytes. The cytotoxic function of p113-121/HLA-A*0201-specific CD8(+) T cells extended into direct killing of splenocytes infected with live Mycobacterium smegmatis expressing ML1419c: both 9mer and 30mer induced CD8(+) T cells that reduced the number of ML1419c-expressing mycobacteria by 95%, whereas no reduction occurred using wild-type M. smegmatis. These data, combined with previous observations in Brazilian cohorts, show that ML1419c p113-121 induces potent CD8(+) T cells that provide protective immunity against M. leprae and B cell help for induction of specific IgG, suggesting its potential use in diagnostics and as a subunit (vaccine) for M. leprae infection.

• Authors: Annemieke Geluk, Susan J F van den Eeden, Karin Dijkman, Louis Wilson, Hee Jin Kim, Kees L M C Franken, John S Spencer, Maria C V Pessolani, Geraldo M B Pereira, Tom H M Ottenhoff
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 3 Pg. 1393-402 (Aug 01 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21705623 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Proteins
• Bacterial Vaccines
• Epitopes, T-Lymphocyte
• HLA-A Antigens
• HLA-A*02:01 antigen
• HLA-A2 Antigen
• ML1419c protein (113-121), Mycobacterium leprae
• Peptide Fragments
• Vaccines, Subunit

Topics

• Amino Acid Sequence
• Animals
• B-Lymphocyte Subsets (immunology, microbiology, pathology)
• Bacterial Proteins (administration & dosage, immunology)
• Bacterial Vaccines (administration & dosage, immunology)
• Cells, Cultured
• Cytotoxicity Tests, Immunologic (methods)
• Epitopes, T-Lymphocyte (administration & dosage, immunology)
• HLA-A Antigens (biosynthesis, genetics, immunology)
• HLA-A2 Antigen
• Humans
• Leprosy (immunology, microbiology, prevention & control)
• Mice
• Mice, Transgenic
• Molecular Sequence Data
• Mycobacterium leprae (immunology, pathogenicity)
• Peptide Fragments (administration & dosage, immunology)
• T-Lymphocytes, Cytotoxic (immunology, microbiology, pathology)
• T-Lymphocytes, Helper-Inducer (immunology, microbiology, pathology)
• Vaccines, Subunit (administration & dosage, immunology)