The influence of type II cytokines in central tolerance
Abstract
While the genetic elements of many autoimmune conditions have been established, many environmental factors remain a mystery. Exposure to certain infections has been implicated as a possible explanation for the significantly different autoimmune disease rates in developing versus industrialized countries. In this manner, type II cytokines have been shown to play a role in peripheral tolerance. The full impact of these type II cytokines in central tolerance and autoimmunity has still yet to be explored. In chapter II, the data indicate that IL-4 and IL-13, dominant type II cytokines, can indeed be found within the thymic microenvironment of healthy C57BL/6 mice. IL-4/IL-13 signaling in ETPs that express the IL-4Rα/IL-13Rα1 heteroreceptor (HR) drives these progenitors to yield thymic resident DCs. These DCs aid in negative selection and the prevention of experimental allergic encephalomyelitis (EAE). In chapter III, the data presented shows that, in contrast to the C57BL/6 strain, HR+ETPs from the type one diabetes (T1D) susceptible NOD strain give rise to T cells. Notably, the NOD thymus shows a dramatic reduction in the steady-state level of IL-4. Indeed, increasing the availability of this cytokine can rescue the lineage fate of HR+ETPs and provide a new pool of thymic DCs. Restoration of NOD HR+ETP lineage fate can improve negative selection, alter the TCRβ repertoire, and ultimately prevent T1D onset. Thus, microenviromental changes within the thymus may be implicated in fine-tuning the balance that dictates the negative selection of autoreactive cells. From this, one may envision that environmental induction of IL-4 and IL-13 may play a role in altering that balance and shifting the tables towards autoimmunity prevention.
Degree
Ph. D.