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Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4

Hye Sun Kuehn1, Weiming Ouyang2, Bernice Lo3,4

  • 1Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Science (New York, N.Y.)
|September 13, 2014
PubMed

Insights

Mutations in Cytotoxic T lymphocyte antigen-4 (CTLA-4) cause severe immune dysregulation in humans, affecting T and B cell balance. This highlights CTLA-4

Area of Science:

  • Immunology
  • Genetics

Background:

  • Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor on immune cells.
  • The effects of CTLA4 mutations in humans were previously unknown.

Purpose of the Study:

  • To investigate the consequences of germline heterozygous mutations in CTLA4 in humans.
  • To understand the role of CTLA-4 in immune system regulation and homeostasis.

Main Methods:

  • Identified germline heterozygous mutations in CTLA4 in subjects with severe immune dysregulation.
  • Compared human CTLA4 haploinsufficiency phenotype with heterozygous Ctla4 mice.
  • Analyzed T regulatory (Treg) cell function, effector T cell activation, and B cell populations.

Main Results:

  • Human CTLA4 haploinsufficiency led to FoxP3(+) regulatory T (Treg) cell dysregulation and effector T cell hyperactivation.
  • Observed lymphocytic infiltration in target organs in patients.
  • Documented progressive loss of circulating B cells, an increase in autoreactive CD21(lo) B cells, and B cell accumulation in nonlymphoid organs.

Conclusions:

  • Inherited human CTLA4 haploinsufficiency reveals a critical quantitative role for CTLA-4 in maintaining T and B lymphocyte homeostasis.
  • CTLA-4 is essential for preventing severe immune dysregulation in humans.

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