The emerging role of ctla4 as a cell-extrinsic regulator of t cell responses

KEY POINTS * Cytotoxic T lymphocyte antigen 4 (CTLA4) and its homologue CD28 are crucial T cell proteins associated with immune regulation. They share the same ligands, CD80 and CD86, which

are present on antigen-presenting cells (APCs). * CTLA4-deficient mice suffer from fatal lymphoproliferative disease and die by 3–4 weeks of age, indicating that CTLA4 is an essential

negative regulator of T cell responses. By contrast, CD28-deficient mice are immunocompromised. * CTLA4 is a highly endocytic receptor that undergoes both recycling to the plasma membrane

and degradation in lysosomes. The cytoplasmic domain, which is required for these functions, is highly conserved in mammals. * CTLA4 is expressed by regulatory T (TReg) cells and activated

conventional T cells. Evidence suggests that CTLA4 is important for TReg cell suppressive function in many settings. * The molecular mechanism of CTLA4 function is still undecided and a

number of cell-intrinsic and cell-extrinsic mechanisms have been proposed. * _In vivo_ studies using bone marrow chimeric mice indicate that CTLA4-deficient T cells are not dysregulated in

the presence of wild-type T cells. This suggests that the main non-redundant function of CTLA4 _in vivo_ is a cell-extrinsic one. * Emerging evidence suggests that one cell-extrinsic

function of CTLA4 may be to downregulate CD80 and CD86 expression on APCs, thereby limiting the ability of APCs to stimulate T cells via CD28. ABSTRACT 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 against the T cell-intrinsic and -extrinsic functions of CTLA4. Access through your institution

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OTHERS CD8 T-CELL SUBSETS: HETEROGENEITY, FUNCTIONS, AND THERAPEUTIC POTENTIAL Article Open access 01 November 2023 LAG3 ASSOCIATES WITH TCR–CD3 COMPLEXES AND SUPPRESSES SIGNALING BY DRIVING

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153–160 (2008). CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We are grateful to S. Sakaguchi and members of the Walker and Sansom groups for helpful discussions. AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * MRC Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, UK Lucy S. K. Walker & David M. Sansom Authors * Lucy S. K.

Walker View author publications You can also search for this author inPubMed Google Scholar * David M. Sansom View author publications You can also search for this author inPubMed Google

Scholar CORRESPONDING AUTHORS Correspondence to Lucy S. K. Walker or David M. Sansom. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RELATED

LINKS RELATED LINKS FURTHER INFORMATION Lucy S. K. Walker's homepage David M. Sansom's homepage GLOSSARY * Peripheral tolerance The generation of tolerance to self for mature T

cells that have left the thymus and are recirculating in the periphery. * Regulatory T cells (TReg cells). Cells that can suppress the activity of other T cells, including autoreactive T

cells. Depletion of TReg cells results in the loss of peripheral tolerance and the development of autoimmune disease. * Clathrin-coated pits Membrane invaginations that contain transmembrane

proteins and a layer of electron-dense clathrin, clathrin adaptors and other proteins on their cytoplasmic faces. These structures bud from the membrane to become clathrin-coated transport

vesicles. * Lipid rafts Structures that are proposed to arise from phase separation of different plasma membrane lipids as a result of the selective coalescence of certain lipids on the

basis of their physical properties. This results in the formation of distinct and stable lipid domains in membranes that might provide a platform for membrane-associated protein

organization. * Non-obese diabetic mice (NOD mice). An inbred strain of mice that spontaneously develops T cell-mediated autoimmune diabetes. The _Idd5_ locus is one region that alters

disease susceptibility in this mouse strain. * Central supramolecular activation cluster (cSMAC). During T cell activation, T cell receptors accumulate into a central cluster (known as the

cSMAC) at the interface between the T cell and the antigen-presenting cell. The cSMAC is surrounded by a ring of LFA1 (known as the pSMAC), and this characteristic receptor organization (the

cSMAC surrounded by the pSMAC) constitutes the mature immunological synapse. * Tetramer staining Biotinylated monomeric MHC molecules are folded _in vitro_ together with a specific peptide

that binds in the binding groove. These peptide–MHC complexes are then tetramerized using a fluorescently labelled streptavidin molecule. The tetramers bind T cells that express T cell

receptors specific for the cognate peptide–MHC complex. They can therefore be used to track antigen-specific T cells by flow cytometry. * Trans-endocytosis The process by which a tightly

associated receptor–ligand complex induces invagination of the plasma membrane and internalization of the complex into the receptor-bearing cell to form a membrane-limited transport vesicle.

* RAG (Recombination activating gene). _Rag1_ and _Rag2_ are expressed in developing lymphocytes. Mice that are deficient for either of these genes fail to produce B and T cells owing to a

developmental block in the gene rearrangement that is necessary for receptor expression. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Walker, L.,

Sansom, D. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. _Nat Rev Immunol_ 11, 852–863 (2011). https://doi.org/10.1038/nri3108 Download citation * Published:

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