Interferon‐alpha regulates the dynamic balance between human activated regulatory and effector T cells: implications for antiviral and autoimmune responses

Abstract

An adequate effector response against pathogens and its subsequent inactivation after pathogen clearance are critical for the maintenance of immune homeostasis. This process involves an initial phase of T-cell effector (Teff) activation followed by the expansion of regulatory T cells (Tregs), a unique cell population that limits Teff functions. However, significant questions remain unanswered about the mechanisms that regulate the balance between these cell populations. Using an in vitro system to mimic T-cell activation in human peripheral blood mononuclear cells (PBMC), we analysed the patterns of Treg and Teff activation, with special attention to the role of type I interferon (IFN-I). Interestingly, we found that IFN-alpha, either exogenously added or endogenously induced, suppressed the generation of CD4(+) FoxP3(HI )IFN-gamma(Neg) activated Tregs (aTregs) while simultaneously promoting propagation of CD4(+) FoxP3(Low/Neg )IFN-gamma(Pos) activated Teffs (aTeffs). We also showed that IFN-alpha-mediated inhibition of interleukin (IL)-2 production may play an essential role in IFN-alpha-induced suppression of aTregs. In order to test our findings in a disease state with chronically elevated IFN-alpha, we investigated systemic lupus erythematosus (SLE). Plasma from patients with SLE was found to contain IFN-I activity that suppressed aTreg generation. Furthermore, anti-CD3 activated SLE PBMCs exhibited preferential expansion of aTeffs with a very limited increase in aTreg numbers. Together, these observations support a model whereby a transient production of IFN-alpha (such as is seen in an early antiviral response) may promote CD4 effector functions by delaying aTreg generation, but a chronic elevation of IFN-alpha may tip the aTeff:aTreg balance towards aTeffs and autoimmunity.