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 August 1, 2011; First published July 1, 2011
Citation Information: J Clin Invest. 2011;121(8):3051-3061. https://doi.org/10.1172/JCI44262.
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Categories: Research Article Vaccines

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 1

s.c. Ova immunization with RA as additive leads to upregulation of gut-homing molecules on antigen-specific T cells in skin-draining ingLNs.

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s.c. Ova immunization with RA as additive leads to upregulation of gut-h...
CFSE-labeled OT-I or DO11.10 cells were adoptively transferred into C57BL/6 or BALB/c mice on day 0. 2 hours later, a single dose of Ova was applied orally or injected s.c. A group of s.c. immunized mice additionally received s.c. injections of 150 μg all-trans RA on days 0, 1, and 2. (A, C, and E) Representative flow cytometry plots obtained on day 3 for α4β7-integrin, CCR9, Foxp3, ESL, and PSL expression on OT-I (DAPI–Ly5.1+Vβ5+CD8β+; A) or DO11.10 (DAPI–CD4+DO11.10+; C and E) T cells activated in the mLN after oral antigen application or in the ingLN after s.c. injection of antigen. Numbers indicate percent positive OT-I or DO11.10 cells. (B, D, and F) Percent α4β7-integrin+, CCR9+, Foxp3+, ESL+, and PSL+ cells among transferred OT-I T cells (B) or DO11.10 T cells (D and F) from the indicated organs. Data were derived from 6–12 mice per group analyzed in 3 independent experiments (OT-I) or 6–10 mice per group analyzed in 2 independent experiments (DO11.10). *P < 0.05; ***P < 0.001.