The role of CTLA-4 in immune regulation (original) (raw)
TCR/CD3 mediated stop-signal is decoupled in T-cells from Ctla4 deficient mice
Immunology Letters, 2008
CTLA-4 is a co-receptor that plays a pivotal role in regulating the threshold for T-cell activation. We recently reported that CTLA-4 ligation can override the stop-signal induced by anti-CD3 ligation [Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, Brewer JM, et al. Reversal of the TCR stop-signal by CTLA-4. Science 2006;313:1972]. While these studies compared CTLA-4 positive and negative T-cells from normal mice, little is known regarding the behaviour of T-cells from diseased Ctla4 deficient mice with auto-proliferative disease. In this study, we show that while activated wild-type and Ctla-4−/− T-cells have similar rates of motility, Ctla-4−/− T-cells show a marked resistance to the induction of a stop-signal by anti-CD3 ligation. By contrast, T-cells from normal mice and CD28 deficient mice underwent a normal slowing of motility in response to anti-CD3 ligation. Our findings identify a fundamental difference between normal versus CTLA-4−/− T-cells from diseased mice in the regulation of motility by anti-CD3 ligation. This dysregulation of motility may contribute to the tissue infiltration and the autoimmune disorder observed in Ctla-4−/− mice.
The role of CTLA-4 in the regulation of T cell immune responses
Immunology and Cell Biology, 1999
Over the past few years a great deal of research has examined how T cell-dependent immune responses are initiated and subsequently regulated. Ligation of the TCR with an antigenic peptide bound to an MHC protein on a professional APC provides the crucial antigen-specific stimulus required for T cell activation. Interaction of CD28 with CD80 or CD86 molecules on APC initiates a costimulatory or second signal within the T cell which augments and sustains T cell activation initiated through the TCR. However, recently it has become clear that T cell immune responses are a result of a balance between stimulatory and inhibitory signals. Cytotoxic T lymphocyteassociated molecule-4 (CTLA-4) is a cell surface molecule that is expressed nearly exclusively on CD4 + and CD8 + T cells. Investigation into the role of CTLA-4 in the regulation of T cell immune responses has revealed that CTLA-4 is a very important molecule involved in the maintenance of T cell homeostasis. In the present review, evidence for the proposed inhibitory role of CTLA-4 is examined and a model suggesting a role for CTLA-4 in both early and late stages of T cell activation is presented.
The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses
Nature Reviews Immunology, 2011
Receptor-ligand interactions. CTLA4 binds the same two ligands -CD80 and CD86 -as CD28. Although not reviewed here, these ligands are mainly expressed on APCs and are generally upregulated following 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.
CTLA-4-Mediated inhibition of early events of T cell proliferation
Journal of immunology (Baltimore, Md. : 1950), 1999
CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated ...
TCR subunit specificity of CTLA-4-mediated signaling
Journal of Leukocyte Biology, 2003
Cytotoxic T-lymphocyte-associated antigen (CTLA)-4 is an activation-induced receptor that down-regulates T cell responses by antagonizing B7dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA-4-mediated negative signaling is unknown. Recently, it has been postulated that CTLA-4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)-chain of the antigen-receptor complex through an lck-dependent recruitment of the Src homology-2-containing tyrosine phosphatase-2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline-inducible CTLA-4 with CD25:TCR-(CD25-) or CD25: CD3-(CD25-) fusion proteins. In these clones, ligation of CD25-or of CD25-with antibodies against CD25 induced full T cell activation, as illustrated by extracellular signal-regulated kinase (ERK) activation and interleukin (IL)-2 production. More importantly, coligation of CTLA-4 with CD25-or of CTLA-4 with CD25-in the respectively transfected clones inhibited ERK activation and IL-2 production, demonstrating that CTLA-4 does not specifically inhibit signals from TCR-but can also inhibit signals from CD3-. Our results suggest that the target specificity of CTLA-4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.
Journal of immunology (Baltimore, Md. : 1950), 1999
Since the functional outcome of effector T lymphocytes depends on a balance between activatory and inhibitory receptors, we studied the ability of CTLA-4 (CD152) to inhibit the cytolytic function of CTL. In 22 TCR alpha/beta+ CD3+ 8+ CTL clones, activation induced by anti-CD3, anti-CD28, or anti-CD2 mAb was inhibited by anti-CD152 mAb in a redirected killing assay. In eight clones inhibition was >40%, in 10 it ranged between 20-40%, and in four it was <20%. This suggests the existence of a clonal heterogeneity as well as for the ability of CTLA-4 to inhibit CD3/TCR-, CD28-, or CD2-mediated CTL activation. To support further this contention, we used an experimental model based upon Ag-specific CTL. Eight Ag-specific T cell clones that lyse autologous EBV-infected B lymphocytes, but are unable to lyse allogeneic EBV-infected B cell lines, were used in a cytolytic assay in which anti-CD152 mAb or soluble recombinant receptor (i.e., CTLA-4 Ig) were included. In this system, at var...