Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice
Swantje I. Hammerschmidt, … , Oliver Pabst, Reinhold Förster
Swantje I. Hammerschmidt, … , Oliver Pabst, Reinhold Förster
Published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3051-3061. https://doi.org/10.1172/JCI44262.
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Research Article

Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice

Abstract

Diarrheal diseases represent a major health burden in developing countries. Parenteral immunization typically does not induce efficient protection against enteropathogens because it does not stimulate migration of immune cells to the gut. Retinoic acid (RA) is critical for gut immunity, inducing upregulation of gut-homing receptors on activated T cells. In this study, we have demonstrated that RA can redirect immune responses elicited by s.c. vaccination of mice from skin-draining inguinal LNs (ingLNs) to the gut. When present during priming, RA induced robust upregulation of gut-homing receptors in ingLNs, imprinting gut-homing capacity on T cells. Concurrently, RA triggered the generation of gut-tropic IgA+ plasma cells in ingLNs and raised the levels of antigen-specific IgA in the intestinal lumen and blood. RA applied s.c. in vivo induced autonomous RA production in ingLN DCs, further driving efficient induction of gut-homing molecules on effector cells. Importantly, RA-supplemented s.c. immunization elicited a potent immune response in the small intestine that protected mice from cholera toxin–induced diarrhea and diminished bacterial loads in Peyer patches after oral infection with Salmonella. Thus, the use of RA as a gut-homing navigator represents a powerful tool to induce protective immunity in the intestine after s.c. immunization, offering what we believe to be a novel approach for vaccination against enteropathogens.

Authors

Swantje I. Hammerschmidt, Michaela Friedrichsen, Jasmin Boelter, Marcin Lyszkiewicz, Elisabeth Kremmer, Oliver Pabst, Reinhold Förster

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Figure 5

RA-supplemented s.c. immunization confers mucosal protection against CT-induced diarrhea and diminishes bacterial loads in Peyer patches after oral Salmonella infection.

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RA-supplemented s.c. immunization confers mucosal protection against CT-...
(A) Mice were treated with CT as in Figure 4 or were left untreated (no immunization). At day 14, mice were challenged orally by gavage with 10 μg CT. 2 hours after challenge, mice were sacrificed, and the weight of the small intestine together with its fluid content was determined. Small intestines of mice receiving neither immunization nor challenge served as controls. Bars represent mean values; symbols represent individual mice pooled from 3 independent experiments. Note the discontinuous y axis. (B) Mice were s.c. immunized with 106 PFA-fixed Salmonella Typhimurium SL1344 lacking the aroA gene (SL1344 ′ˆ†aroA) on days 0 and 2. A group of s.c. immunized mice was additionally s.c. injected with RA on days 0, 1, 2, 3, 4, 7, 8, and 9. On day 14, mice were orally inoculated with 7 × 107 or 4 × 109 wild-type Salmonella Typhimurium SL1344. 2 days after infection, bacterial loads were determined in single Peyer patches. Bars represent median values; symbols represent individual Peyer patches from 3 (7 × 107) or 4 (4 × 109) mice per group. Numerals within the graph indicate the number of sterile Peyer patches. *P < 0.05; **P < 0.01.