The immunological components that control resolution of Salmonella infection and successful vaccination are poorly defined. In a model of chronic gastrointestinal infection, we observed that the lymphotoxin (LT) pathway is essential for the clearance and resolution of primary infection of attenuated Salmonella enterica Typhimurium strain SL3261 ΔaroA. Using gnotobiotic mice, we show that LTβ receptor (LTβR) signaling and the microbiota are required to promote clearance of attenuated S. enterica Typhimurium from the gut lumen. We also found that LTβR signaling was required for successful immunization and subsequent protection upon challenge with a virulent strain of S. enterica Typhimurium. LTβR signaling promoted the development of specific IgG recognizing S. enterica Typhimurium during infection, as well as Ag-driven IFN-γ responses. B cell- and type 3 innate lymphoid cell-derived LT signaling, but not T cell-derived LT, contributes to anti-S. enterica Typhimurium protective responses. Collectively, our results suggest that LT signaling is essential for multiple steps of anti-S. enterica Typhimurium immune responses.
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