The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses

  title={The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses},
  author={Lucy S. K. Walker and David M. Sansom},
  journal={Nature Reviews Immunology},
The T cell protein cytotoxic T lymphocyte antigen 4 (CTLA4) was identified as a crucial negative regulator of the immune system over 15 years ago, but its mechanisms of action are still under debate. It has long been suggested that CTLA4 transmits an inhibitory signal to the cells that express it. However, not all the available data fit with a cell-intrinsic function for CTLA4, and other studies have suggested that CTLA4 functions in a T cell-extrinsic manner. Here, we discuss the data for and… 

on Regulatory T Cells Function Predicts Its Suppressive Behavior A Transendocytosis Model of CTLA-4

Clear rules for the inhibitory function of CTLA-4 on regulatory T cells are revealed, which are predicted by its ability to remove ligands from APC, which is highly effective at low numbers of APC or low levels of ligand.

Cutting Edge: Cell-Extrinsic Immune Regulation by CTLA-4 Expressed on Conventional T Cells

It is shown that Tconv-expressed CTLA-4 can function in a cell-extrinsic manner in vivo, and this observation provides a potential resolution to the above paradox and suggests CTla-4 function on both Tconv and regulatory T cells can be achieved through cell- Extrinsics mechanisms.

A transendocytosis perspective on the CD28/CTLA-4 pathway.

A Transendocytosis Model of CTLA-4 Function Predicts Its Suppressive Behavior on Regulatory T Cells

Clear rules are revealed for the inhibitory function of CTLA-4 on regulatory T cells, which are predicted by its ability to remove ligands from APC, which is highly effective at low numbers of APC or low levels of ligand.

Moving CTLA-4 from the trash to recycling

Evidence is provided that an intracellular protein, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) controls CTLA-4 expression and thereby influences immune self-tolerance.

PRO136ALA CTLA4 Mutation

To test whether this mutation is causal in the phenotype of the patient, the CRISPR/Cas9-mediated genome editing will be used to clone the mutation into a regulatory T cell-like cell line and use the edited cell line for functional studies.

Measuring CTLA-4-Dependent Suppressive Function in Regulatory T Cells.

This chapter provides protocols for isolation of human monocytes and their differentiation into dendritic cells (DC), purification of conventional and regulatory T-cell populations, and the assembly of CTLA-4-dependent Treg suppression assays, in the hope that this will offer a reliable platform for dissecting the biology of CTla-4 on Treg and for testing reagents aimed at modulating CTlake-4 function.

The soluble isoform of CTLA‐4 as a regulator of T‐cell responses

It is suggested that the immune system exploits the different CTLA‐4 isoforms for either intrinsic or extrinsic regulation of T‐cell activity, which is responsible for at least some of the inhibitory effects previously ascribed to the membrane‐bound isoform.

CTLA-4: a moving target in immunotherapy.

The biology of the CD28/CTLA-4 pathway is focused on as a framework for understanding the impacts of therapeutic manipulation of this pathway.



The reverse stop-signal model for CTLA4 function

  • C. Rudd
  • Biology
    Nature Reviews Immunology
  • 2008
In this Opinion article, the strengths and weaknesses of the current models are outlined, and a new 'reverse stop-signal model' to account for CTLA4 function is presented.

CTLA-4 can function as a negative regulator of T cell activation.

Molecular basis of T cell inactivation by CTLA-4.

CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation, and these findings have broad implications for the negative regulation of T cell function and T cell tolerance.

Reversal of the TCR Stop Signal by CTLA-4

It is shown that CTLA-4 increases T cell motility and overrides the T cell receptor (TCR)–induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells, which suggests a fundamentally different model of reverse stop signaling.

CTLA-4 suppresses the pathogenicity of self antigen–specific T cells by cell-intrinsic and cell-extrinsic mechanisms

It is demonstrated that both cell-intrinsic and non–cell-autonomous actions of CTLA-4 operate to maintain T cell tolerance to a self antigen.

Lack of Intrinsic CTLA-4 Expression Has Minimal Effect on Regulation of Antiviral T-Cell Immunity

Regulation of memory T-cell survival and homeostatic proliferation, as well as secondary responses, was equivalent in virus-specific CTLA4+/+ and CTL-A-4−/− T- cell populations, suggesting lack of CTLA-4 expression by antigen-specific T cells can be compensated for by extrinsic factors in the presence of CTla-4expression by other cells.

CTLA-4 Differentially Regulates T Cell Responses to Endogenous Tissue Protein Versus Exogenous Immunogen1

It is shown that CTLA-4 only modestly reduces responses to Ag administered with adjuvant, but dramatically inhibits responses to the same Ag expressed transgenically as a tissue self protein.

Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule.

In vitro, when the B7 molecule on the surface of antigen-presenting cells binds to the T cell surface molecules CD28 and CTLA-4, a costimulatory signal for T cell activation is generated. CTLA4Ig is

Enhancement of Antitumor Immunity by CTLA-4 Blockade

In vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors, and this rejection resulted in immunity to a secondary exposure to tumor cells, suggesting that blockade of the inhibitory effects of CTLA4 can allow for, and potentiate, effective immune responses against tumor cells.