Typhoid and Non-Typhoidal Salmonellosis (NTS) are systemic diseases that annually cause 1 million global deaths. Greater understanding of protective immunity to Salmonella will be required if safe and effective vaccines for these diseases are to become a reality. Our application examines the fundamental biology of protective CD4 Th1 cells elicited by live vaccines that provide robust protective immunity. Our experimental approach is unique in that it utilizes natural water contamination challenge, uses a mouse model where CD4 Th1 cells participate actively in bacterial clearance, and allows for direct visualization of endogenous Salmonella-specific CD4 T cells, using reagents recently developed by our laboratory. Our application specifically proposes to, (i) examine the role of non-cognate Th1 cell stimulation in Salmonella clearance, (ii) determine the role of tissue-resident memory cells in the elimination of persistent bacteria, and (iii) examine whether these two functional aspects of Th1 cell memory can be induced by a sub-unit immunization strategy. Understanding these issues will increase our knowledge of Salmonella-specific CD4 Th1 cell biology and could be vital for the development of safe and effective vaccines for typhoid and NTS.