CD4+ T cells and their derived cytokines are major contributors for the induction and regulation of antigen-specific mucosal IgA responses. In this study, we have characterized mucosal immune system of CD4 knockout (CD4-/-) mice to understand the exact role of CD4+ T cells for the induction and regulation of mucosal immune responses. Phenotypic analysis of T cells revealed that increased numbers of CD4-CD8- (double negative:DN) T cells occur in both systemic and mucosal compartments. Analysis of frequency of Ig producing cells in spleen (SP) and lamina propria (LP) showed that lower numbers of IgM producing cells were detected, while essentially identical numbers of IgG and IgA producing cells were seen in SP of CD4-/- mice when compared with control mice (CD4+/+). However, IgA secreting cells in LP of CD4-/- mice were significantly lower than that of the control group. When CD4-/- mice were orally immunized with ovalbumin (OVA) and cholera toxin (CT) as mucosal adjuvant, OVA- and CT-B-specific mucosal IgA responses were not detected. In contrast, serum IgG and IgM responses were induced in CD4-/- mice. These results suggest that CD4+ T cells play an important role for the induction of antigen-specific mucosal IgA responses when protein antigens are administered orally. We are currently examining mucosal immune responses in CD4-/- mice using different oral delivery systems.