title: Early CD44(hi)CD4+ and CD44(hi)CD8+ T cell numbers and the absence of mannose-rich glycoconjugates determine the protective outcome of anti-leishmanial immunity.
abstract: Vaccination remains the best hope for control of all forms of leishmaniasis, and the development of a safe and effective vaccine is a critical global public-health priority. Our previous work showed that immunization with non-persistent phosphomannomutase-deficient (DeltaPMM) Leishmania major parasites confers significant protection in susceptible BALB/c mice due to increased T-cell numbers and suppression of IL-10 and IL-13 early during infection. Here, we complemented the DeltaPMM L. major parasites with human PMM2 to determine whether we could further improve the protection. Complemented DeltaPMM parasites have restored glycoconjugate biosynthesis, while retaining avirulence of the parental knockout strain. Immunization with hPMM2 add-back parasites showed similar Th1/Th2 cytokine profiles to that observed in DeltaPMM-vaccinated mice. However, the numbers of the activated CD4+CD44(hi) and CD8+CD44(hi) T cells recruited to the draining lymph nodes early after Leishmania infection were reduced, leading to decreased protection following hPMM2-immunization. Thus, the magnitude of T-cell responses early in the infection and the absence of mannose-rich glycoconjugates determine the protective outcome of anti-leishmanial immunity.
authors.affiliation: Infection and Immunity Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde, Parkville 3052, Australia. kedzierski@wehi.edu.au
authors.forename: L
authors.initials: L
authors.lastname: Kedzierski
authors.forename: J M
authors.initials: JM
authors.lastname: Curtis
authors.forename: K
authors.initials: K
authors.lastname: Kedzierska
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006001:Glycoconjugates / Q000276:immunology; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology*; D018320:Leishmania major / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D054332:Leishmaniasis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000517:prevention & control*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008358:Mannose / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017875:Phosphotransferases (Phosphomutases) / Q000172:deficiency / Q000235:genetics; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D006001:Glycoconjugates; D018960:Hyaluronan Receptors; D054332:Leishmaniasis Vaccines; D014614:Vaccines, Synthetic; D017875:Phosphotransferases (Phosphomutases); C052799:phosphomannomutase; D008358:Mannose