Description

CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.

Structure

The protein contains an extracellular V domain, a transmembrane domain, and a cytoplasmic tail. Alternate splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. The intracellular domain is similar to that of CD28, in that it has no intrinsic catalytic activity and contains one YVKM motif able to bind PI3K, PP2A and SHP-2 and one proline-rich motif able to bind SH3 containing proteins. The first role of CTLA-4 in inhibiting T cell responses seem to be directly via SHP-2 and PP2A dephosphorylation of TCR-proximal signalling proteins such as CD3 and LAT. CTLA-4 can also affect signalling indirectly via competing with CD28 for CD80/86 binding. CTLA-4 can also bind PI3K, although the importance and results of this interaction are uncertain.

Functions

CTLA4 is a member of the immunoglobulin superfamily that is expressed by activated T cells and transmits an inhibitory signal to T cells. CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28 thus enabling it to outcompete CD28 for its ligands. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. CTLA4 is also found in regulatory T cells and contributes to their inhibitory function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4.

The mechanism by which CTLA-4 acts in T cells remains somewhat controversial. Biochemical evidence suggested that CTLA-4 recruits a phosphatase to the T cell receptor (TCR), thus attenuating the signal. This work remains unconfirmed in the literature since its first publication. 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.

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. Although it is reversible upon T regulatory cell disengagement, this sequestration of essential cytoskeletal components causes a lethargic state of DCs, leading to reduced T cell priming. This suggests Treg-mediated immune suppression is a multi-step process. In addition to CTLA-4 CD80/CD86 interaction, fascin-dependent polarization of the cytoskeleton towards DC-Treg immune synapse may play a pivotal role.

CTLA-4 may also function via modulation of cell motility and/or signaling through PI3 kinase. Early multiphoton microscopy studies observing T-cell motility in intact lymph nodes appeared to give evidence for the so-called ‘reverse-stop signaling model’. In this model CTLA-4 reverses the TCR-induced ‘stop signal’ needed for firm contact between T cells and antigen-presenting cells.

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Immunotherapy: Open Access                                                   

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