CD4+ memory–phenotype T cells decline over time when generated in response to acute infections cleared by other components of the immune system. Therefore, it was of interest to assess the stability of CD4+ T cells during a persistent Salmonella infection, which is typical of persistent phagocytic infections that are controlled by this lymphocyte subset. We found that CD4+ T cells specific for Salmonella peptide: MHC class II (MHCII) ligands were numerically stable for> 1 y after initial 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. The persistent population consisted of multifunctional Th1 cells that induced PD-1 and became exhausted when transferred to hosts expressing the specific peptide: MHCII ligand in all parts of the body. Thus, persistent infection of phagocytes produced a CD4+ T cell population that was stably maintained by low-level peptide: MHCII presentation.