The susceptibility and T cell responses of Bcg resistant (C3H/He) and susceptible (C57BL/6) strains of mice were compared at various intervals after intraperitoneal infection with Mycobacterium paratuberculosis. Both mouse strains developed non-specific macrophage activation by 10-15 days after infection. Mycobacterial counts progressively decreased in the C3H/He mice while remaining relatively constant in the C57BL/6 mice. Lymphocytes were harvested from peritoneal exudate cells (PEC) spleens, intestinal epithelial lymphocytes (IEL), lamina propria lymphocytes (LPL), Peyer's patches (PP) and mesenteric lymph nodes (MLN) and labeled with monoclonal antibodies to CD3, CD4, CD8, gamma/delta TCR, CD25, and CD44 for flow cytometric analysis. Innate strain differences in the proportion of T cell subsets were detected in both control and infected mice. Uninfected C3H/He mice had higher proportions of CD3+ cell sin the spleen, MLN, PP, LPL, ands IEL while uninfected C57BL/6 mice had higher proportions of gamma/delta+ and CD8+ cells. Marked increases in gamma/delta+ and CD8+ cells were detected in the PEC's and other tissues of both strains in response to infection. Higher CD4/CD8 T cell ratios were observed in most lymphoid tissues of C3H/He mice, while increased proportions of CD8 and/or gamma/delta T cells were present in C57BL/6 mice. Expression of CD25 by PEC's decreased in C57BL/6 mice and increased in C3H/He mice in response to infection. Expression of CD44 was higher in C57BL/6 mice throughout the study and increased in both strains in response to infection. These results suggest that decreased proportions of CD4+ cells and a downregulation of IL-2 production or function may play a role in the persistence of Mycobacterium paratuberculosis infections.