Type II Cytokines Guide Early Thymic Progenitor Lineage Choice and Influence Negative Selection of Myelin-Reactive T cells

Abstract

Abstract IL-4 and IL-13 are considered anti-inflammatory cytokines and have been effective in sustaining peripheral T cell tolerance and modulation of experimental allergic encephalomyelitis (EAE), an animal model for human multiple sclerosis. Herein, evidence is presented suggesting that both IL-4 and IL-13 contribute to central tolerance of myelin-reactive T cells and restrain the development of EAE. Indeed, IL-4 and IL-13 signaling through their IL-4Rα/IL-13Rα1 heteroreceptor (HR) activates STAT6 transcription factor to inhibit the potential of early thymic progenitors (ETPs) to mature to T cells. In parallel, the cytokines trigger phosphorylation of STAT1 which promote ETPs to give rise to myeloid cells most of which belong to the CD11c+CD8α+ dendritic cell (DC) subset which reside in the thymus. These ETP-derived thymic resident DCs are able to function as antigen presenting cells (APCs) and are proven effective in supporting central tolerance of myelin-reactive T cells in vivo leading to resistance against the development of EAE. Since IL-4 and IL-13 are usually induced in response to parasitic infection or exposure to allergen, the findings are interpreted to mean that these cytokines provide a link between environmental triggers and central tolerance, a concept that bodes well with theories of the hygiene hypothesis and the discrepancies in autoimmune diseases incidence among undeveloped and western countries