Constitutive Clathrin-mediated Endocytosis of CTLA-4 Persists during T Cell Activation

Qureshi, Omar; Kaur, Satdip; Hou, Tie Zheng; Jeffery, Louisa; Poulter, Natalie S.; Briggs, Zoe; Kenefeck, Rupert; Willox, Anna K.; Royle, Stephen; Rappoport, Joshua Z.; Sansom, David M.

doi:10.1074/jbc.m111.304329

Cited by 135 publications

(129 citation statements)

References 36 publications

(50 reference statements)

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…This observation prompted the idea that CTLA-4 could potentially act as a physical ligand-capturing device thereby depleting shared CD28-ligands from antigen-presenting cells. Subsequent experiments revealed that the entire ligand (either CD80 or CD86) including its cytoplasmic domain could be transferred to the CTLA-4 recipient cell and that internalized ligands were subsequently degraded consistent with the known pattern of CTLA-4 intracellular trafficking (34). This process occurs in vivo and is seen only in CD4þ CD25þ T cells (including, but not restricted to Tregs) and removal of ligands by transendocytosis can therefore be considered as a cell-extrinsic form of ligand blockade.…”

Section: Cd28 and Ctla-4 Functions Are Tightly Connectedmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

View full text Add to dashboard Cite

T cell activation is a key event in the adaptive immune system and vital in the generation of protective cellular and humoral immunity. Activation is required to generate CD4 effector T cell responses and provide help for B cell and cytotoxic T cell responses. While defective T responses to foreign antigen result in infectious pathology, over-reactive T cell responses against self-antigens result in autoimmunity and, in a transplantation setting, tissue rejection. Understanding how T cell activation is normally regulated is critical to therapeutic intervention and the CD28/CTLA-4 (CD152) pathway represents the initial activation checkpoint in molecular terms. In particular, while the CTLA-4 pathway is well established as an essential regulator of self-reactivity, its mechanism of action is still uncertain. Such mechanistic issues are important given its central position in T cell activation and the increasing number of therapeutic modalities aimed at manipulating the CD28/CTLA-4 pathway. Here, we provide an updated view of CTLA-4 biology, reviewing the established features of the system and highlighting its interplay with CD28. We then discuss how recent progress in our understanding of this pathway affects our interpretations following intervention. A Functional Overview of the CD28/CTLA-4 Pathway CD28 is expressed on the surface of the majority of na€ ıve CD4 and CD8 T cells and is the major costimulatory molecule in initial T cell activation. Together with engagement of the T cell receptor CD28 ligation results in the augmentation of many aspects of T cell-mediated immunity (1-3). Consequently, mice deficient in CD28 show an array of immune defects including impaired T cell activation, a lack of T cell help for B cells and poor memory T cell responses, all highlighting the importance of CD28 costimulation in the generation of effective T cell responses and immune memory.The immune stimulatory features of the CD28 pathway are triggered by engagement of two well-described ligands found on antigen-presenting cells (4). The two ligands CD80 (B7/BB1 or B7-1) and CD86 (B7-2) were, until recently, thought to be the sole ligands for CD28 and CTLA-4; however, there are recent reports that human (but not mouse) CD28 and CTLA-4, can also bind to the ICOS ligand (5). In addition, the PD-1 ligand, PD-L1 can also interact with CD80 (6). The significance of these novel interactions is still emerging and will not be discussed further here. Importantly, the expression of CD80 and CD86 is up-regulated in response to inflammatory stimuli including Toll-like receptor stimulation. As such, up-regulation of ligands is seen as a key link between innate ''danger'' signals and the triggering of an effective adaptive immune response (7). Despite structural and affinity differences (8) which would suggest functional differences, to date, the current view is that CD80 and CD86 have largely redundant or overlapping functions as represented in Figure 1 (9,10).In addition to binding to CD28, both CD80 and CD86 also bind to the inhibitory p...

show abstract

Section: Cd28 and Ctla-4 Functions Are Tightly Connectedmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

View full text Add to dashboard Cite

show abstract

“…Nonetheless, Synj1 is activated by calcium influx and calcineurin, leading to its binding with endophili and thus facilitating clathrin-mediated endocytosis (30,31,52,54). Furthermore, although Synj1 expression in T cells has not been analyzed, the calcineurin pathway is critical for T cell responses, while clathrinmediated endocytosis also plays an important role in TCR and CTLA-4 endocytosis following T cell activation (55,56). It is therefore possible that upon alloantigenic stimulation, a calcineurindependent process leads to an increased expression and activation of Synj1 that modulates T cell responses via TCR/CTLA-4 endocytosis.…”

Section: Figurementioning

confidence: 99%

Allogeneic T cell responses are regulated by a specific miRNA-mRNA network

et al. 2013

View full text Add to dashboard Cite

“…We have previously shown that uptake of antibodies and ligands by CTLA-4 at 37°C is a convenient measure of CTLA-4 trafficking. 25 By gating on Foxp3 1 cells, this provides an estimate of CTLA-4 function in Tregs.…”

Section: Org Frommentioning

confidence: 99%

“…24 Subsequently, trafficking of CTLA-4-containing vesicles through the cell involves both recycling to the plasma membrane and degradation in lysosomes. 25 Accordingly, disturbances in trafficking can result in defective CTLA-4 expression. This issue has been recently highlighted by the discovery that LRBA affects CTLA-4 trafficking and lysosomal degradation.…”

Section: Introductionmentioning

confidence: 99%

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

Hou

Verma

Wanders

et al. 2017

Blood

Self Cite

View full text Add to dashboard Cite

show abstract

Constitutive Clathrin-mediated Endocytosis of CTLA-4 Persists during T Cell Activation

Cited by 135 publications

References 36 publications

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Allogeneic T cell responses are regulated by a specific miRNA-mRNA network

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

Contact Info

Product

Resources

About