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Sci Transl Med. 2015 Oct 21;7(310):310ra167. doi: 10.1126/scitranslmed.aac5477.

Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells.

Author information

1
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada.
2
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada. Institute of Tropical Medicine, Third Military Medical University, Chongqing 400038, China.
3
Laboratory of Transmission, Control and Immunobiology of Infections, Pasteur Institute of Tunis, Tunis 1002, Tunisia.
4
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
5
Manitoba Centre for Proteomics and Systems Biology, Department of Internal Medicine, University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba R3E 3P4, Canada.
6
Department of Clinical Biochemistry, Laboratory Sciences, Third Military Medical University, Chongqing 400038, China.
7
Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
8
Department of Immunology, Third Military Medical University, Chongqing 400038, China.
9
National Reference Centre for Parasitology, Department of Medicine, Division of Infectious Diseases, McGill University, Montreal, Quebec H3G 1A4, Canada.
10
Department of Epidemiology, University of Iowa, Iowa City, IA 52242 USA.
11
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610065, China.
12
Molecular Immunology and Vaccine Research Laboratory, Pasteur Institute of Iran, Tehran 13164, Iran.
13
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada. Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. jude.uzonna@umanitoba.ca.

Abstract

There is currently no clinically effective vaccine against leishmaniasis because of poor understanding of the antigens that elicit dominant T cell immunity. Using proteomics and cellular immunology, we identified a dominant naturally processed peptide (PEPCK335-351) derived from Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK). PEPCK was conserved in all pathogenic Leishmania, expressed in glycosomes of promastigotes and amastigotes, and elicited strong CD4(+) T cell responses in infected mice and humans. I-A(b)-PEPCK335-351 tetramer identified protective Leishmania-specific CD4(+) T cells at a clonal level, which comprised ~20% of all Leishmania-reactive CD4(+) T cells at the peak of infection. PEPCK335-351-specific CD4(+) T cells were oligoclonal in their T cell receptor usage, produced polyfunctional cytokines (interleukin-2, interferon-γ, and tumor necrosis factor), and underwent expansion, effector activities, contraction, and stable maintenance after lesion resolution. Vaccination with PEPCK peptide, DNA expressing full-length PEPCK, or rPEPCK induced strong durable cross-species protection in both resistant and susceptible mice. The effectiveness and durability of protection in vaccinated mice support the development of a broadly cross-species protective vaccine against different forms of leishmaniasis by targeting PEPCK.

PMID:
26491077
DOI:
10.1126/scitranslmed.aac5477
[Indexed for MEDLINE]

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