Differential susceptibility and maturation of thymocyte subsets during Salmonella Typhimurium infection: Insights on the roles of glucocorticoids and Interferon-gamma

Abstract

The thymus is known to atrophy during infections; however, a systematic study of changes in thymocyte subpopulations has not been performed. This aspect was investigated, using multi-color flow cytometry, during oral infection of mice with Salmonella Typhimurium (S. Typhimurium). The major highlights are: First, a block in the developmental pathway of CD4- CD8- double negative (DN) thymocytes is observed. Second, CD4+ CD8+ double positive (DP) thymocytes, mainly in the DP1 (CD5lo CD3lo) and DP2 (CD5hi CD3int), but not DP3 (CD5int CD3hi), subsets are reduced. Third, single positive (SP) thymocytes are more resistant to depletion but their maturation is delayed, leading to accumulation of CD24 hi CD3 hi SP. Kinetic studies during infection demonstrated differences in sensitivity of thymic subpopulations: Immature single positive (ISP) > DP1, DP2 > DN3, DN4 > DN2 > CD4+ > CD8+. Upon infection, glucocorticoids (GC), inflammatory cytokines, e.g. Ifnγ 3, etc are induced, which enhance thymocyte death. Treatment with RU486, the GC receptor antagonist, increases the survival of most thymic subsets during infection. Studies with Ifnγ-/-mice demonstrated that endogenous Ifnγ 3 produced during infection enhances the depletion of DN2-DN4 subsets, promotes the accumulation of DP3 and delays the maturation of SP thymocytes. The implications of these observations on host cellular responses during infections are discussed.