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

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.

• Authors: Zhirong Mou, Jintao Li, Thouraya Boussoffara, Hiroyuki Kishi, Hiroshi Hamana, Peyman Ezzati, Chuanmin Hu, Weijing Yi, Dong Liu, Forough Khadem, Ifeoma Okwor, Ping Jia, Kiyomi Shitaoka, Shufeng Wang, Momar Ndao, Christine Petersen, Jianping Chen, Sima Rafati, Hechmi Louzir, Atsushi Muraguchi, John A Wilkins, Jude E Uzonna
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 310 Pg. 310ra167 (Oct 21 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26491077 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Antigens, Protozoan
• Receptors, Antigen, T-Cell
• Phosphoenolpyruvate Carboxykinase (ATP)

Topics

• Animals
• Antigens, Protozoan (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Leishmania (classification, enzymology, immunology)
• Mice
• Mice, Inbred C57BL
• Phosphoenolpyruvate Carboxykinase (ATP) (metabolism)
• Receptors, Antigen, T-Cell (genetics)