Removal of regulatory T cells prevents secondary chronic infection but increases the mortality of subsequent sub-acute infection in sepsis mice

// Ruichao Huo 1,* Lili Wang 1,* , Xiaoya Wang 1 , Yong Zhao 2 , Yi Wang 2 , Xiaomin Zhao 1 , Lingling Chang 1 , Shan-lu Liu 3 , Dewen Tong 1 , Hai Zhang 2 and Yong Huang 1 1 College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China 2 Laboratory Animal Center, Fourth Military Medical University, Xi’an, Shaanxi, China 3 Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, MO, United States of America * These authors have contributed equally to this work Correspondence to: Yong Huang, email: // Hai Zhang, email: // Keywords : sepsis, immunosuppression, lymphocyte, immunotherapeutic approach, secondary infection, Immunology and Microbiology Section, Immune response, Immunity Received : November 11, 2015 Accepted : February 16, 2016 Published : February 24, 2016 Abstract The immunosuppression following initial septic insult impairs resistance to secondary infection. Modulation of lymphocytes population may help to develop an effective therapeutic strategy. In this study, lipopolysaccharide (LPS)-induced endotoxemia was employed as the initial septic insult. 24 hours later, mice underwent cecal ligation and puncture to induce chronic or sub-acute peritonitis. Potential usefulness of T regs deletion antibody (anti-CD25) in improving LPS-induced immunosuppression and the survival of subsequent different infections were evaluated. LPS injection induced lymphocyte loss and led to decreased IL-6, TNF-α and IFN-γ, and weakened bacteria clearance upon chronic peritonitis at 24 h post-LPS, whereas reconstitution with lymphocytes reversed these changes. LPS-induced T regs expansion contributed to T and NK cells decrease in number and activity during sepsis. Depletion of T regs using anti-CD25 antibodies partly prevented lymphocyte loss and increased the responses of T and NK cells to subsequent stimulation, resulting in significantly increased bacterial clearance and survival in a 2-hit model of chronic peritonitis, but which significantly increased early mortality upon subsequently sub-acute infection. Yet, using lower dosage of anti-CD25 antibodies to moderate down-regulate T regs levels could partly improve bacterial clearance and survival in either chronic or sub-acute infection. These results demonstrate that using anti-CD25 antibodies to deplete T regs can ameliorate immunosuppression through increasing T cells and NK cells responses in sepsis, which is beneficial for preventing subsequently chronic infection, but will probably bring some deleterious effects for subsequent sub-acute infection.