Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Abstract

Cytotoxic T lymphocyte antigen–4 (CTLA-4) is an inhibitory receptor found on immune cells. The consequences of mutations in CTLA4 in humans are unknown. We identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation from four unrelated families. Whereas Ctla4 heterozygous mice have no obvious phenotype, human CTLA4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells, hyperactivation of effector T cells, and lymphocytic infiltration of target organs. Patients also exhibited progressive loss of circulating B cells, associated with an increase of predominantly autoreactive CD21lo B cells and accumulation of B cells in nonlymphoid organs. Inherited human CTLA4 haploinsufficiency demonstrates a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis.

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

“…[15][16][17] In fact, some patients identified with PIK3C have already been demonstrated to respond to sirolimus in a pilot trial. 16 Although we are unable to test our patients for these newly described mutations, their identification support additional rationale for the use of sirolimus, and may help identify those patients more likely to respond based on disease biology.…”

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Regulatory T cells in cancer immunotherapy

“…In mice, Treg-specific deletion of CTLA-4 elicits systemic hyper-proliferation of Tconv cells and fatal autoimmune diseases affecting multiple organs, including severe myocarditis [20]. Recently, heterozygous CTLA-4 mutations in humans were identified in patients with multiple autoimmune symptoms accompanied by impaired suppressive function of Treg cells [21,22]. As CTLA-4 has much higher affinity than CD28 for their common ligands CD80 and CD86, CTLA-4 expressed by Treg cells may physically outcompete CD28 on Tconv [23,24].…”