The role of major histocompatibility complex (MHC) class I- and class II-restricted functions in Helicobacter pylori infection and immunity upon oral immunization was examined in vivo. Experimental challenge with H. pylori SS1 resulted in significantly greater (P </= 0.025) colonization of MHC class I and class II mutant mice than C57BL/6 wild-type mice. Oral immunization with H. pylori whole-cell lysates and cholera toxin adjuvant significantly reduced the magnitude of H. pylori infection in C57BL/6 wild-type (P = 0.0083) and MHC class I knockout mice (P = 0.0048), but it had no effect on the H. pylori infection level in MHC class II-deficient mice. Analysis of the anti-H. pylori antibody levels in serum showed a dominant serum immunoglobulin G1 (IgG1) response in immunized C57BL/6 wild-type and MHC class I mutant mice but no detectable serum IgG response in MHC class II knockout mice. Populations of T-cell-receptor (TCR) alphabeta+ CD4(+) CD54(+) cells localized to gastric tissue of immunized C57BL/6 wild-type and MHC class I knockout mice, but TCRalphabeta+ CD8(+) cells predominated in the gastric tissue of immunized MHC class II-deficient mice. These observations show that CD4(+) T cells engaged after mucosal immunization may be important for the generation of a protective anti-H. pylori immune response and that CD4(+) CD8(-) and CD4(-) CD8(+) T cells regulate the extent of H. pylori infection in vivo.