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 (CD5loCD3lo) and DP2 (CD5hiCD3int), but not DP3 (CD5intCD3hi), subsets are reduced. Third, single positive (SP) thymocytes are more resistant to depletion but their maturation is delayed, leading to accumulation of CD24hiCD3hi 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, 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 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.
Highlights
To CD8+ T cells[4,5,6]
Typhimurium-induced thymic atrophy, we have shown that DPs, but not SPs, undergo apoptosis[17]
Typhimurium infection leads to loss of DN and DP thymocyte subsets
Summary
To CD8+ T cells[4,5,6]. During selection, self-reactive TCR clones are deleted and cell surface CD24 and CD69 are down-modulated before mature SP T cells egress the thymus as recent thymic emigrants[7,8]. Several factors are responsible for infection-induced thymic atrophy. Several reports have demonstrated the roles of GCs either by adrenalectomy or administration of RU486, a GC receptor signalling antagonist[15,16,17] Another set of players that are important are inflammatory cytokines[14,17,20,21]. Cytokines e.g. IL6 and its family members[23], and other molecules, e.g. reactive oxygen species[24], signalling molecules[25], and caspases[26] play important roles during infection-induced thymic atrophy. Typhimurium is a Gram negative bacterium that survives and replicates within intracellular compartments in host cells It causes gastroenteritis in humans but leads to typhoid-like disease in mice, similar to that caused by S. The roles of GC and endogenous Ifnγwere investigated and the implications of this study, in the context of immune consequences during infection-induced thymic atrophy, are discussed
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