Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity

Abstract

Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.

Tr1 Cells and the Counter-Regulation of Immunity: Natural Mechanisms and Therapeutic Applications

“…tTregs are important early in life, and loss of their function is life-threatening at very young age, as it is demonstrated in patients with Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome, bearing FOXP3 mutations. tTregs expansion and function is IL-2 dependent, as shown by both IL-2 or CD25 knock-out (KO) mice and CD25-deficient patients, whose phenotype resembles FOXP3 deficiency (Goudy et al 2013). On the other hand, IL-10 KO mice have originally revealed the importance of this cytokine in the gut homeostasis and in preventing overwhelming inflammation (Kuhn et al 1993).…”

Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy

“…CD25 deficiency properties shared with IPEX include chronic eczema, enteropathy, lymphoproliferation, and autoimmunity disorders such as alopecia, diabetes mellitus, thyroiditis, and autoimmune hemolytic anemia [101][102][103]. CD25 deficiency is permissive to Treg cell differentiation, with normal count of FOXP3+ Treg cells found in circulation [104].…”

IL-21 signalling via STAT3 primes human naïve B cells to respond to IL-2 to enhance their differentiation into plasmablasts

“…Peripheral blood was collected from patients with mutations in STAT3, STAT1, IL21R, IL2RG, and IL2RA. 21,23,32,33 Epstein-Barr virus-transformed lymphoblastoid B-cell lines (LCLs) were established as described. 23 Human experiments were approved by the relevant institutional ethics committees at St. Vincent's Hospital, Royal Prince Alfred Hospital, Sydney Children's Hospital Network, Westmead Hospital, The Canberra Hospital (in Australia), as well as at National Institute for Allergy and Infectious Diseases/National Institutes of Health and Rockefeller University.…”