What did we learn from CTLA‐4 insufficiency on the human immune system?

Abstract

Cytotoxic‐T‐lymphocyte‐antigen‐4 (CTLA‐4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA‐4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA‐4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA‐4‐mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA‐4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty‐eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA‐4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA‐4‐insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA‐4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life‐threatening, treatment‐resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA‐4 insufficiency causes severe disease taught us that the amount of CTLA‐4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology‐causing activated T lymphocytes in CTLA‐4‐insufficient patients are antigen‐specific is an unsolved question. CTLA‐4, in addition, has a role in autoimmune diseases and cancer. Anti‐CTLA‐4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA‐4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA‐4 molecule and immune dysregulation disorders.