Critical Role for TCR Signal Strength and MHC Specificity in ThPOK-Induced CD4 Helper Lineage Choice.

Sustained TCR signaling is critical for ThPOK induction in MHC class II (MHCII)-signaled thymocytes leading to the CD4 helper lineage commitment. ThPOK suppresses the cytotoxic program in the signaled thymocytes and is shown to be necessary and sufficient for the CD4 helper lineage choice. Accordingly, loss and gain of ThPOK function redirects MHCII- and MHC class I (MHCI)-signaled thymocytes into the CD8 cytotoxic and CD4 helper lineage, respectively. However, the impact of a defined ThPOK level on the CD4 helper lineage choice of MHCII- and MHCI-specific thymocytes and the role of TCR signaling in this process is not evaluated. Equally, it is not clear if suppression of the cytotoxic program by ThPOK is sufficient in redirecting MHCI-restricted thymocytes into the CD4 helper lineage. In this study, we have investigated CD8 to CD4 helper lineage redirection in three independent ThPOK overexpressing transgenic mouse lines. Our analysis shows that one of the transgenic lines, despite overexpressing ThPOK compared with wild-type CD4 mature T cells and compromising cytotoxic program, failed to redirect all MHCI-signaled thymocytes into the CD4 helper lineage, resulting in the continued presence of CD8+ mature T cells and the generation of a large number of double negative mature T cells. Critically, the same ThPOK transgene completely restored the CD4 helper lineage commitment of MHCII-specific Thpok -/- thymocytes. Importantly, augmenting TCR signaling significantly enhanced the ThPOK-mediated CD4 helper lineage choice of MHCI-specific thymocytes but was still substantially less efficient than that of MHCII-specific thymocytes expressing the same amount of ThPOK. Together, these data suggest that the ThPOK-induced CD4 helper lineage commitment is strongly influenced by TCR signal strength and MHC specificity of developing thymocytes.

Atorvastatin Reduces the Survival of Candida albicans-Infected BALB/c Mice.

Several antimicrobial and immunosuppressive effects have been attributed to the statins class of antihyperlipidemia drugs. Several studies have also indicated clinical benefits for the use of statins during the management of infections and sepsis. To assess whether the immunosuppressive effects of statins outweigh their antimicrobial effects during a fungal infection BALB/c mice were administered Candida albicans via intraperitoneal injection. These mice received either a co-injection of atorvastatin along with the infection, were treated with one injection of atorvastatin per day for 5 days prior to infection, or were infected and then treated with one injection of atorvastatin for 5 days afterward. Groups that received C. albicans without being treated with atorvastatin were included as controls along with a group that only received phosphate-buffered saline. Mouse survival was then monitored; additionally, serum IFN-γ and IL-4 levels were determined by enzyme linked immunosorbent assay to assess pro-inflammatory and pro-humoral responses, respectively. Atorvastatin administration was capable of altering mouse survival rate with the lowest rate (11.1%) being observed in the group treated for 5 days prior to infection with atorvastatin compared to mice infected but not treated with atorvastatin (44.4%). IFN-γ and IL-4 levels were depressed in all C. albicans-infected groups treated with atorvastatin. The possibility that statin administration may suppress or modulate particular components of the immune system during an infection in man should be further explored in large randomized controlled trials.