RT Journal Article SR Electronic T1 Identification of broadly conserved cross-species protective Leishmania antigen and its responding CD4+ T cells JF Science Translational Medicine FD American Association for the Advancement of Science SP 310ra167 OP 310ra167 DO 10.1126/scitranslmed.aac5477 VO 7 IS 310 A1 Mou, Zhirong A1 Li, Jintao A1 Boussoffara, Thouraya A1 Kishi, Hiroyuki A1 Hamana, Hiroshi A1 Ezzati, Peyman A1 Hu, Chuanmin A1 Yi, Weijing A1 Liu, Dong A1 Khadem, Forough A1 Okwor, Ifeoma A1 Jia, Ping A1 Shitaoka, Kiyomi A1 Wang, Shufeng A1 Ndao, Momar A1 Petersen, Christine A1 Chen, Jianping A1 Rafati, Sima A1 Louzir, Hechmi A1 Muraguchi, Atsushi A1 Wilkins, John A. A1 Uzonna, Jude E. YR 2015 UL http://stm.sciencemag.org/content/7/310/310ra167.abstract AB Leishmaniasis is a potentially fatal disease caused by a protozoal parasite transmitted through sand fly bites. There is currently no vaccine, but affected individuals are resistant to further infection, suggesting vaccination is possible. Now, Mou et al. have found that vaccination with an immunodominant antigen—phosphoenolpyruvate carboxykinase (PEPCK)—protects against leishmaniasis. The authors identified PEPCK by examining peptides that could elicit memory T cell responses from healed but not uninfected animals. PEPCK was conserved in all pathogenic Leishmania and induced immune responses in both infected mice and human cells. Protection in mice was effective across species and was durable, supporting testing of a PEPCK-based vaccine in humans.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-Ab–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.