Differences in CD80 and CD86 transendocytosis reveal CD86 as a key target for CTLA-4 immune regulation.

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself.

Regulation of CTLA-4 recycling by LRBA and Rab11.

CTLA-4 is an essential regulator of T-cell immune responses whose intracellular trafficking is a hallmark of its expression. Defects in CTLA-4 trafficking due to LRBA deficiency cause profound autoimmunity in humans. CTLA-4 rapidly internalizes via a clathrin-dependent pathway followed by poorly characterized recycling and degradation fates.

CD80 on Human T Cells Is Associated With FoxP3 Expression and Supports Treg Homeostasis.

CD80 and CD86 are expressed on antigen presenting cells (APCs) and their role in providing costimulation to T cells is well established. However, it has been shown that these molecules can also be expressed by T cells, but the significance of this observation remains unknown. We have investigated stimuli that control CD80 and CD86 expression on T cells and show that in APC-free conditions around 40% of activated, proliferating CD4 T cells express either CD80, CD86 or both.

CD86 Is a Selective CD28 Ligand Supporting FoxP3+ Regulatory T Cell Homeostasis in the Presence of High Levels of CTLA-4.

CD80 and CD86 are expressed on antigen presenting cells and are required to engage their shared receptor, CD28, for the costimulation of CD4 T cells. It is unclear why two stimulatory ligands with overlapping roles have evolved. CD80 and CD86 also bind the regulatory molecule CTLA-4.

Characterization of CTLA4 Trafficking and Implications for Its Function.

CTLA4 is an essential negative regulator of T-cell immune responses and a key checkpoint regulating autoimmunity and antitumor responses. Genetic mutations resulting in quantitative defects in the CTLA4 pathway are also associated with the development of immune dysregulation syndromes in humans. It has been proposed that CTLA4 functions to remove its ligands CD80 and CD86 from opposing cells by a process known as transendocytosis.

CTLA-4: a moving target in immunotherapy.

CD28 and CTLA-4 are members of a family of immunoglobulin-related receptors that are responsible for various aspects of T-cell immune regulation. The family includes CD28, CTLA-4, and ICOS as well as other proteins, including PD-1, BTLA, and TIGIT. These receptors have both stimulatory (CD28, ICOS) and inhibitory roles (CTLA-4, PD-1, , and TIGIT) in T-cell function.

Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations.

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disorders.

RasGAP mediates neuronal survival in Drosophila through direct regulation of Rab5-dependent endocytosis.

The GTPase Ras can either promote or inhibit cell survival. Inactivating mutations in Drosophila RasGAP (encoded by vap), a Ras GTPase-activating protein, lead to age-related brain degeneration. Genetic interactions implicate the epidermal growth factor receptor (EGFR)-Ras pathway in promoting neurodegeneration but the mechanism is not known.

The in vitro characterization of a gelatin scaffold, prepared by cryogelation and assessed in vivo as a dermal replacement in wound repair.

A sheet gelatin scaffold with attached silicone pseudoepidermal layer for wound repair purposes was produced by a cryogelation technique. The resulting scaffold possessed an interconnected macroporous structure with a pore size distribution of 131 ± 17 μm at one surface decreasing to 30 ± 8 μm at the attached silicone surface. The dynamic storage modulus (G') and mechanical stability were comparable to the clinical gold standard dermal regeneration template, Integra®.