The role of regulatory T cells in the resistance of CCR4 knockout mice during severe sepsis

Background

Studies reveal that regulatory T (T_reg) cells control immune responses; therefore these responses must be controlled to enable effective protection against infections and cancer. CCR4 knockout (CCR4^-/-) mice are more resistant to lipopolysaccharide shock. So, our aim is to study the mechanisms involved in the resistance of CCR4^-/- mice subjected to severe sepsis by cecal ligation and puncture (CLP) and how T_reg cells modulate this effect.

Methods

C57/BL6 mice were subjected to a CLP model, whereby the cecum was partially ligated and punctured nine times with a 21 G needle. Sham-operated mice were used as control. Mice subjected to CLP and sham surgery were treated with antibiotic from 6 hours after surgery until 3 days.

Results

CCR4^-/- mice subjected to CLP presented an increase in the survival rate (78%) compared with wild-type mice (17%), and presented a marked improvement in the innate response concerning neutrophil migration to the peritoneum and lung, bacterial load and cytokine levels compared with wild-type mice. Besides, T_reg cells from CCR4^-/- CLP mice did not inhibit proliferation of T effector cells as observed for T_reg cells from wild CLP mice, at a proportional ratio of T effector: T_reg cells. Interesting, T_reg cells from CCR4^-/- CLP mice inhibit 30% of neutrophil migration to bronchoalveolar lavage when co-injected with fungal challenge as secondary infection in sham recipient mice, while the cells T_reg from wild CLP mice inhibit 80%, much more than expected.

Conclusion

These results suggest that T_reg cells from CCR4^-/- mice did not present a suppressive response and this could be an important factor in their survival. These results are strong evidence for the role of T_reg cells in immunosuppression following severe sepsis.