Anti-retroviral therapy (ART) in AIDS patients often causes the severe inflammatory diseases accompanying the recovery of CD4+ T cell number, designated as immune reconstitution inflammatory syndrome (IRIS). Opportunistic infection of various pathogens, such as nontuberculous mycobacterium (NTM), is thought to be a trigger to induce hyper immune response, but the underlying mechanisms of disease development have not been fully elucidated. To address this issue, we established the IRIS model by Mycobacterium avium complex (MAC) pulmonary infection in mice, which were temporarily depleted CD4+ T cells by anti-CD4 mAb administration. These mice (termed IRIS mice) showed the severe inflammation with highly expression of inflammatory cytokines (IL-1β, IL-6, and IFN-γ), robust infiltration of leucocytes, and enhanced granuloma development in lungs. The number of regulatory T cells in IRIS mice was not fully restored although induction of Th1 cells was comparable to MAC infected control mice. IRIS mice also displayed marked increase of IFN-γ secreted CD8+ T cells in spleen and draining lymph nodes. Depletion of CD8+ T cells in IRIS mice attenuated the lung inflammation and leucocytes infiltration, indicating that CD8+ T cells play a critical role for disease development. In conclusion, impairment of regulatory function of CD4+ T cells during ART in AIDS patients might enhance the CD8+ T cell activation by opportunistic infection, causing the severe inflammatory responses such as IRIS.