03298nas a2200481   4500000000100000008004100001260001600042653002400058653002300082653002500105653002300130653002300153653002000176653003600196653002700232653001900259653001900278653001100297653001200308653000900320653002100329653002800350653001500378653002200393653002900415653003400444653002200478100001200500700001400512700001600526700001500542700001000557700001900567700001500586700001200601700001400613700001300627245014700640300001300787490000800800520199400808022001402802       2011                            d  c2011 Aug 0110aAmino Acid Sequence10aAnimals, poisonous10aB-Lymphocyte Subsets10aBacterial Proteins10aBacterial Vaccines10aCells, Cultured10aCytotoxicity Tests, Immunologic10aEpitopes, T-Lymphocyte10aHLA-A Antigens10aHLA-A2 Antigen10aHumans10aleprosy10aMice10aMice, Transgenic10aMolecular Sequence Data10atratamento10aPeptide Fragments10aT-Lymphocytes, Cytotoxic10aT-Lymphocytes, Helper-Inducer10aVaccines, Subunit1 aGeluk A1 aFranken K1 aOttenhoff T1 aSpencer JS1 aKim H1 aPessolani MC V1 aPereira GM1 aEeden S1 aDijkman K1 aWilson L00aML1419c peptide immunization induces Mycobacterium leprae-specific HLA-A*0201-restricted CTL in vivo with potential to kill live mycobacteria.  a1393-4020 v1873 a<p>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.</p>  a1550-6606