[8] In November 1995, the labs of Tak Wah Mak and Arlene Sharpe independently published their findings on the discovery of the function of CTLA-4 as a negative regulator of T-cell activation, by knocking out the gene in mice.

More recent work has suggested that CTLA-4 may function in vivo by capturing and removing CD80 and CD86 from the membranes of antigen-presenting cells, thus making these unavailable for triggering of CD28.

[18] In addition to that, it has been found that dendritic cell (DC) - Treg interaction causes sequestration of Fascin-1, an actin-bundling protein essential for immunological synapse formation and skews Fascin-1–dependent actin polarization in antigen presenting DCs toward the Treg cell adhesion zone.

In addition to CTLA-4 CD80/CD86 interaction, fascin-dependent polarization of the cytoskeleton towards DC-Treg immune synapse may play a pivotal role.

[20] Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’.

This may cause a dysregulation of the immune system and may result in lymphoproliferation, autoimmunity, hypogammaglobulinemia, recurrent infections, and may slightly increase one’s risk of lymphoma.

The organs affected by autoimmunity vary but include thrombocytopenia, hemolytic anemia, thyroiditis, type I diabetes, psoriasis, and arthritis.

This “variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.

Penetrance is said to be incomplete when some individuals fail to express the trait and seem completely asymptomatic, even though they carry the allele.

[26][27][31] Once a diagnosis is made, the treatment is based on an individual’s clinical condition and may include standard management for autoimmunity and immunoglobulin deficiencies.

Regular administration of abatacept improved the patient’s severe anemia and diarrhea (3L/day) and brought 3-year-long hospitalization to an end.

Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA-4 (using antagonistic antibodies against CTLA such as ipilimumab—FDA approved for melanoma in 2011—as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer).

[5] The 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".

[34] CTLA-4 has been shown to interact with: This article incorporates text from the United States National Library of Medicine, which is in the public domain.