Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells.
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.
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada.
Zhirong
Z
Mou
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.
Jintao
J
Li
Laboratory of Transmission, Control and Immunobiology of Infections, Pasteur Institute of Tunis, Tunis 1002, Tunisia.
Thouraya
T
Boussoffara
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Hiroyuki
H
Kishi
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Hiroshi
H
Hamana
Manitoba Centre for Proteomics and Systems Biology, Department of Internal Medicine, University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba R3E 3P4, Canada.
Peyman
P
Ezzati
Department of Clinical Biochemistry, Laboratory Sciences, Third Military Medical University, Chongqing 400038, China.
Chuanmin
C
Hu
Department of Clinical Biochemistry, Laboratory Sciences, Third Military Medical University, Chongqing 400038, China.
Weijing
W
Yi
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada.
Dong
D
Liu
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada.
Forough
F
Khadem
Department of Medical Microbiology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
Ifeoma
I
Okwor
Department of Immunology, College of Medicine, University of Manitoba, Winnipeg, Manitoba R3T 0T5, Canada.
Ping
P
Jia
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Kiyomi
K
Shitaoka
Department of Immunology, Third Military Medical University, Chongqing 400038, China.
Shufeng
S
Wang
National Reference Centre for Parasitology, Department of Medicine, Division of Infectious Diseases, McGill University, Montreal, Quebec H3G 1A4, Canada.
Momar
M
Ndao
Department of Epidemiology, University of Iowa, Iowa City, IA 52242 USA.
Christine
C
Petersen
Department of Parasitology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610065, China.
Jianping
J
Chen
Molecular Immunology and Vaccine Research Laboratory, Pasteur Institute of Iran, Tehran 13164, Iran.
Sima
S
Rafati
Laboratory of Transmission, Control and Immunobiology of Infections, Pasteur Institute of Tunis, Tunis 1002, Tunisia.
Hechmi
H
Louzir
Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
Atsushi
A
Muraguchi
Manitoba Centre for Proteomics and Systems Biology, Department of Internal Medicine, University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba R3E 3P4, Canada.
John A
JA
Wilkins
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.
Jude E
JE
Uzonna
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D007891:Leishmania / Q000145:classification / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics
D000953:Antigens, Protozoan; D011948:Receptors, Antigen, T-Cell; D019764:Phosphoenolpyruvate Carboxykinase (ATP)