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Optimal protection against Salmonella infection requires noncirculating memory.

ABSTRACT: While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteristics of tissue residence and did not acquire robust protective immunity. Using a YFP-IFN-? reporter system, we identified Th1 cells in the liver of immunized mice that displayed markers of tissue residence, including P2X7, ARTC2, LFA-1, and CD101. Adoptive transfer of liver memory cells after ARTC2 blockade increased protection against highly virulent bacteria. Taken together, these data demonstrate that noncirculating memory Th1 cells are a vital component of immunity to Salmonella infection and should be the focus of vaccine strategies.

SUBMITTER: Benoun JM

PROVIDER: S-EPMC6187142 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Optimal protection against Salmonella infection requires noncirculating memory.

Benoun Joseph M JM Peres Newton G NG Wang Nancy N Pham Oanh H OH Rudisill Victoria L VL Fogassy Zachary N ZN Whitney Paul G PG Fernandez-Ruiz Daniel D Gebhardt Thomas T Pham Quynh-Mai QM Puddington Lynn L Bedoui Sammy S Strugnell Richard A RA McSorley Stephen J SJ

Proceedings of the National Academy of Sciences of the United States of America 20180925 41

While CD4 Th1 cells are required for resistance to intramacrophage infections, adoptive transfer of Th1 cells is insufficient to protect against Salmonella infection. Using an epitope-tagged vaccine strain of Salmonella, we found that effective protection correlated with expanded Salmonella-specific memory CD4 T cells in circulation and nonlymphoid tissues. However, naive mice that previously shared a blood supply with vaccinated partners lacked T cell memory with characteri ...[more]

PMID: 30254173

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Project description:Brucellosis remains the most common zoonotic disease globally. Currently no vaccines for humans exist, and conventional brucellosis vaccines for livestock fail to confer complete protection; hence, an improved vaccine is needed. Although Brucella infections primarily occur following a mucosal exposure, vaccines are administered parenterally. Few studies have considered mucosal vaccinations, or even targeting of tissue-resident memory T (TRM) cells. TRM cells protect against viral infections, but less is known of their role in bacterial infections, and even less for brucellosis. Oral prime, nasal boost with a newly developed Brucella abortus double mutant (znBAZ) confers nearly complete protection against pulmonary challenge with wild-type (wt) B. abortus 2308, and its protective efficacy is >2800-fold better than the RB51 vaccine. Vaccination with znBAZ potently stimulated CD8+ T cells, whereas mucosal vaccination with RB51 induced mostly CD4+ T cells. Subsequent analysis revealed these pulmonary CD44+ CD69+ CD8+ T cells to be either CD103+ or CD103- TRM cells, and these sequestered to the lung parenchyma as CXCR3lo and to the airways as CXCR3hi. Both CD8+ TRM subsets contained single-positive IFN-? and TNF-?, as well as, polyfunctional cells. IL-17-producing CD8+ TRM cells were also induced by znBAZ vaccination, but in vivo IL-17 neutralization had no impact upon protection. In vivo depletion of CD4+ T cells had no impact upon protection in znBAZ-vaccinated mice. In contrast, CD4+ T cell depletion reduced RB51's protective efficacy in spleens and lungs by two- and three-logs, respectively. Although anti-CD8 mAb-treated znBAZ-vaccinated mice showed a significantly reduced pulmonary efficacy, this treatment failed to completely deplete the lung CD8+ T cells, leaving the CD103+ and CD103- CD8+ TRM cell ratios intact. Only znBAZ-vaccinated CD8-/- mice were fully sensitive to pulmonary challenge with virulent wt B. abortus 2308 since CD8+ TRM cells could not be induced. Collectively, these data demonstrate the key role of mucosal vaccination for the generation of CD8+ TRM cells in protecting against pulmonary challenge with virulent B. abortus.

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Optimal protection against Salmonella infection requires noncirculating memory.

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Optimal protection against <i>Salmonella</i> infection requires noncirculating memory.

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