Uncovering the role of interleukin-3 in autoimmunity

Abstract

Hematopoietic growth factors govern the production and survival of our immune cells, which are derived from hematopoietic stem and progenitor cells residing in bone marrow niches throughout our body. Also functioning as mediators of cellular communication, or ‘cytokines’, hematopoietic growth factors instruct our immune cells to perform necessary functions both in the steady-state and during inflammatory bouts to protect us from infection or injury. However, in settings of inflammatory and autoimmune disease, the same growth factors can participate in propagating detrimental inflammation. Studying hematopoietic growth factors/cytokines is important for discovering therapeutic strategies that support host defense and ameliorate inflammation depending upon the disease context. Interleukin-3 (IL-3) is a colony-stimulating factor (CSF) growth factor and cytokine long- known for its ability to support myeloid cell growth from hematopoietic progenitors in vitro. In type 2 inflammation, IL-3 amplifies inflammatory reactions which expel parasites but also drives harmful inflammatory reactions in the context of allergic diseases. Moreover, in inflammatory and autoimmune diseases, IL-3 appears to fuel pro-inflammatory myeloid cell production and function, however, the cytokine remains understudied in such disease contexts. We, therefore, sought to investigate the specific role of IL-3 in autoimmunity. Interestingly, IL-3 shares a receptor subunit with granulocyte-macrophage colony-stimulating factor (GM-CSF), a well-known pro-inflammatory cytokine in autoimmunity. We thus initially hypothesized that IL-3 exacerbates autoimmune inflammation and tested this hypothesis using two well-established models of T cell-mediated autoimmunity involving the heart and central nervous system (CNS), respectively. In this thesis, we describe an autoimmune disease-promoting role for IL-3; namely, we found that IL-3 locally exacerbates inflammation in myocardial and CNS tissues in autoimmune myocarditis and encephalomyelitis, respectively, leading to downstream disease sequelae. We characterized the hematopoietic producers of IL-3 in both models as CD4+ T helper cells. We also identified Ly6Chigh monocytes, MHCII+ macrophages, and monocyte-derived dendritic cells as the major IL-3 receptor (IL-3R)- expressing responders to IL-3 in autoimmune target tissues. Ultimately, we found that CD4+ T helper cells and IL-3R+ myeloid cells communicate via IL-3 signaling, leading to myeloid cells’ production of CCL2, CCL7, and CCL12, which fuels an inflammatory cellular amplification loop important for sustaining autoimmunity.