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Vaccine. 2018 Jul 5;36(29):4188-4197. doi: 10.1016/j.vaccine.2018.06.005. Epub 2018 Jun 8.

Flagellin is a Th1 polarizing factor for human CD4+ T cells and induces protection in a murine neonatal vaccination model of rotavirus infection.

Author information

1
Centro de Investigación en Dinámica Celular (IICBA), Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico.
2
Inmunología, Centro de Investigaciones Biomédicas (CINBIO), Centro Singular de Investigación de Galicia, Instituto de Investigación Sanitaria Galicia Sur, Universidad de Vigo, Campus Universitario de Vigo, 36310 Vigo, Spain.
3
Facultad de Nutrición, Universidad Autonoma del Estado de Morelos, Cuernavaca, Morelos, Mexico.
4
Facultad de Medicina, Universidad Autonoma del Estado de Morelos, Cuernavaca, Morelos, Mexico.
5
CISEI Instituto Nacional de Salud Publica, Cuernavaca, Morelos, Mexico.
6
Centro de Investigación en Dinámica Celular (IICBA), Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico. Electronic address: santana@uaem.mx.

Abstract

Neonates have an increased susceptibility to infections, particularly those caused by intracellular pathogens, leading to high morbidity and mortality rates. This is partly because of a poor response of neonatal CD4+ T cells, leading to deficient antibody production and a low production of IFN-γ, resulting in deficient elimination of intracellular pathogens. The poor memory response of human neonates has underpinned the need for improving vaccine formulations. Molecular adjuvants that improve the response of neonatal lymphocytes, such as the ligands of toll-like receptors (TLRs), are attractive candidates. Among them, flagellin, the TLR5 ligand, is effective at very low doses; prior immunity to flagellin does not impair its adjuvant activity. Human CD4+ and CD8+ T cells express TLR5. We found that flagellin induces the expression of IFN-γ, IL-1β and IL-12 in mononuclear cells from human neonate and adult donors. When human naïve CD4+ T cells were activated in the presence of flagellin, there was high level of expression of IFN-γ in both neonates and adults. Furthermore, flagellin induced IFN-γ production in Th1 cells obtained from adult donors; in the Th2 population, it inhibited IL-4 cytokine production. Flagellin also promoted expression of the IFN-γ receptor in naive CD4+ T cells from neonates and adults. To test the adjuvant capacity of flagellin in vivo, we used a murine neonate vaccination model for infection with rotavirus, a pathogen responsible for severe diarrhea in young infants. Using the conserved VP6 antigen, we observed an 80% protection against rotavirus infection in the presence of flagellin, but only in those mice previously primed in the neonatal period. Our data suggest that flagellin could be an attractive adjuvant for achieving a Th1 response.

KEYWORDS:

CD4(+) T cells; Flagellin; Neonatal vaccines; Rotavirus; TLR5; VP6

PMID:
29891347
DOI:
10.1016/j.vaccine.2018.06.005
[Indexed for MEDLINE]

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