The primary goal of immunology is to maximize the immune system's potential to control or eliminate harmful infection. This can be achieved through vaccination, though current vaccine strategies have had limited success when targeting CD4+ T cell-dependent cellular immunity to intracellular infections. CD4+ T cells are cells of the adaptive immune system that use clonally-distributed T cell antigen receptors (TCRs) to recognize 9 amino acid peptide antigens bound to Major Histocompatibility Complex II (MHCII) molecules on host cells. Each vertebrate animal contains a large set of CD4+ T cells, each with a unique TCR and generated before infection. Here, we studied the repertoire of CD4+ T cells in mice to better understand why some non-mouse (foreign) peptide:MHCII ligands (p:MHCII) stimulate stronger immune response than others. We found that naïve CD4+ T cell populations specific for different foreign p:MHCII vary considerably in size and that large naïve populations produce more effector cells during an immune response than small ones. Because the T cell repertoire in a mouse is generated by removal in the thymus of clones with TCRs that recognize mouse p:MHCII, we tested the possibility that the size of a given naïve foreign peptide-specific T cell population is shaped by negative selection on similar mouse (self) peptides. We found that identity at 4 amino acid positions was all that was required for two MHCII-binding nonamer peptides to bind the same TCR. This basic principle allowed in silico approaches to reveal that the number of cells in a foreign peptide-specific T cell population was inversely related to the number of MHCII-binding self peptides with the same 4 TCR contact amino acids. Therefore, the size of a given naïve foreign p:MHCII-specific T cell population is shaped by negative selection due to TCR cross-reaction on similar self p:MHCII ligands. We next explored the effect of a large foreign p:MHCII-specific T cell population on immunity. Because CD4+ T cells protect hosts from infections that have evolved to persist in the phagosomes of infected cells, it was of interest to test this issue during a persistent Salmonella enterica serovar Typhimurium (ST) infection. Remarkably, I found that this one large foreign p:MHCII-specific T cell population played a large role in controlling ST infection, despite the likely presentation of many other ST-derived p:MHCII. This control was associated with numerical and functional stability of the large foreign p:MHCII-specific T cell population for greater than a year after oral infection. This stability was associated with peptide:MHCII-driven proliferation by a small number of T cells in the secondary lymphoid organs that harbored bacteria. Thus, my work could instruct novel subunit vaccine strategies to target large naïve CD4+ T cell populations and maintain their responses with longer-lasting peptide delivery.