Type II Cytokines in the Thymic Microenvironment Influence T cell Negative Selection in Type One Diabetes

Abstract

Abstract From an autoimmunity perspective type II cytokines, such as IL-4 and IL-13, are viewed as anti-inflammatory because of their ability to foster peripheral tolerance. This report provides evidence that credits these cytokines with yet another attribute that pertains to central T cell tolerance. Specifically, a subset of early thymic progenitors (ETPs) which expresses the IL-4Rα/IL-13Rα1 heteroreceptor (HR) adopts a pattern of lineage commitment with guidance from IL-4/IL-13 in the thymic microenvironment. Indeed, IL-4 and IL-13 direct HR+ ETPs towards the myeloid lineage by inhibiting their T cell potential and promoting maturation towards dendritic cells (DCs). Given that DCs can contribute to negative selection of self-reactive T cells, IL-4 and IL-13 in the microenvironment would impact the development of autoreactive T cells in two ways: diminished T cell generation from ETPs and elimination of self-reactive lymphocytes by DC-driven negative selection. This postulate is supported by findings indicating that in the C57BL/6 mouse strain, where IL-4 and IL-13 are readily available in the thymic microenvironment, HR+ ETPs give rise to myeloid cells that contribute to negative T cell selection leading to resistance against experimental allergic encephalomyelitis (EAE). In contrast, in NOD mice IL-4 and IL-13 availability is limited and HR+ETPs give rise to T cells; perhaps leading to diminished negative selection of T cells with diabetogenic potential and higher susceptibility to type 1 diabetes (T1D). These previously unrecognized observations extend the function of type II cytokines to central tolerance and offer a possible link of the environment to the development of autoimmunity as envisioned by hygiene hypothesis theories.