Interleukin-7: a key Mediator in T Cell-driven Autoimmunity, Inflammation, and Tissue Destruction

Abstract

IL-7, expressed by stromal cells in primary lymphoid organs, is known for its critical role in the development and homeostatic expansion of T cells in humans and mice. IL-7 is equally important for B cell development in human and mice, but only in mice seems critical for B cell development and expansion. Recent studies demonstrate that this potent immunostimulatory cytokine is overexpressed in inflamed tissues of patients with (rheumatic) autoimmune diseases and that expression levels correlate with clinical parameters of disease. In inflamed tissues several cell types, including macrophages, dendritic cells, and fibroblasts produce IL-7. IL-7 primarily acts on T cells that abundantly express the IL-7 receptor and that are increased at the inflammatory sites, and predominantly induces Th1 and Th17-associated cytokine secretion. IL-7-mediated T cell-dependent activation of macrophages, dendritic cells and B cells is accompanied by up regulation of T cell differentiating factors, chemokines, adhesion/co-stimulatory molecules and catabolic cytokines and enzymes. Moreover, overexpression of IL-7 is associated with ectopic lymphoid aggregate formation, corresponding with the capacity of IL-7 to induce LTβ and TNFα and to activate innate lymphoid tissue inducer cells. Additionally, IL-7 promotes T cell-driven osteoclastogenesis and fibroblast activation, processes involved in tissue destruction in chronic inflammation. Altogether this suggests that IL-7 is an important proinflammatory mediator in several chronic (rheumatic) inflammatory autoimmune diseases. The substantial amelioration of inflammation and immunopathology in experimental animal models for these diseases by blocking IL-7(receptor) supports this role of IL-7 and demonstrates that IL-7 and its receptor represent novel targets for immunotherapy.

Phenotypic Alterations Involved in CD8+ Treg Impairment in Systemic Sclerosis

“…On the contrary, CD127 expression increased in CD8+ Tregs generated from SSc patients. Our observation is consistent with recent literature data indicating that IL-7 may play a significant role in numerous T cell-driven chronic inflammatory autoimmune diseases, and that this cytokine likely regulates the proliferation of autoreactive T cells (27). …”

Tributyltin exposure alters cytokine levels in mouse serum

“…Mice exposed to 200 or 100 nM TBT tended to show decreases in the serum levels of IL-7, while those exposed to 25 nM showed significant increases. IL-7 functions in T- and B-cell development, acting as a growth factor (Bikker et al 2012). It is produced by non-hematopoietic stromal cells, rather than leukocytes such as T-cells, B-cells and NK cells.…”

Decreased serum level of IL-7 in patients with active Graves’ disease

“…Moreover, IL-7 mediates T cell-dependent activation of macrophages, dendritic cells and B cells, and upregulates numerous T cell cytokines and enzymes. The overexpression of IL-7 is associated with ectopic lymphoid aggregate formation and promotes T cell-driven osteoclastogenesis and fibroblast activation, processes involved in tissue destruction in chronic inflammation [17]. The hypothesis that IL-7 Table 1 Baseline demographic and clinical characteristics of 37 GD patients and 16 healthy controls; (X ± SD).…”