Identification of an Alternative CTLA-4 Ligand Costimulatory for T Cell Activation

Hathcock, Karen S.; László, Glória; Dickler, Howard B.; Bradshaw, Jeff; Linsley, Peter S.; Hodes, Richard J.

doi:10.1126/science.7694361

Cited by 503 publications

(271 citation statements)

References 14 publications

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“…With regard to in vivo relevance, a number of studies have suggested that antigen presentation by resting B cells causes T cell anergy instead of priming (33,34). This finding is of particular interest because resting B cells express high levels of ICAM-1 but minimal levels of B7 (35). Even for dendritic cells, it is notable that immature subsets can express low levels of B7 with significant levels of ICAM-1 (36,37).…”

Section: Discussionmentioning

confidence: 99%

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells

Ragazzo¹

2000

Proceedings of the National Academy of Sciences

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The mechanisms controlling induction of anergy at the level of naïve CD4 ؉ T cells are poorly understood but thought to reflect limited contact with costimulatory molecules during T cell antigen receptor (TCR) ligation. To clarify this question, naïve TCR transgenic CD4 ؉ cells were exposed to specific peptide presented by transfected antigen-presenting cells (APC) expressing MHC class II molecules with defined accessory molecules. Significantly, culturing CD4 ؉ cells with APC expressing MHC II plus peptide alone elicited early TCR signaling but failed to induce either proliferation or anergy. Culture with APC expressing MHC II plus B7 molecules led to strong proliferation and T cell priming but no anergy. In marked contrast, conspicuous induction of anergy occurred after T cell culture with APC expressing MHC class II and intercellular adhesion molecule-1 (ICAM-1). Thus, at the level of naïve CD4 ؉ cells, anergy induction appears to reflect selective contact with APC expressing ICAM-1 in the absence of B7.rodent ͉ adhesion molecules T he outcome of initial T cell contact with antigen (immunity or tolerance) is important both for assuring adequate responses to infectious pathogens and preventing inappropriate responses to self-antigens. The mechanisms controlling self͞nonself discrimination are not fully understood but may hinge on the function of costimulatory molecules. For normal immune responses, it is clear that T cell stimulation involves not only T cell receptor (TCR) recognition of peptide-MHC complexes but also interactions between costimulatory receptors and their ligands on professional antigen-presenting cells (APC). CD28 molecules are the bestcharacterized costimulatory receptors on T cells. Binding of CD28 to its B7 ligands complements TCR ligation to promote immunological synapses between T cells and APC (1, 2) and ultimately the induction of sustained proliferative responses, cytokine production (e.g., IL-2 and IL-4), and expression of molecules promoting cell survival (e.g., Bcl-x L ) (3-8).When T cells recognize antigen in the absence of costimulation, however, the results are quite different. For primed T cells, TCR stimulation (signal 1) without concomitant coligation of CD28 (signal 2) induces T cell functional unresponsiveness or anergy characterized by the failure to proliferate or make IL-2 on reexposure to antigen presented in the context of optimal costimulation (8-12).Although this paradigm for anergy induction is well established for T cell clones and lines, there is considerable controversy as to whether delivery of signal 1 alone also induces anergy at the level of naïve CD4 ϩ T cells. In the studies of Lechler and colleagues (13), exposure of unprimed CD4 ϩ T cells to immobilized anti-CD3 mAb was shown to render the surviving cells profoundly unresponsive to subsequent mitogen stimulation. The relevance of this finding to physiological recognition of MHC-peptide on normal APC is somewhat unclear, because the affinity of the TCR for peptide-MHC complexes is more than 1,000-fold lowe...

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Section: Discussionmentioning

confidence: 99%

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells

Ragazzo¹

2000

Proceedings of the National Academy of Sciences

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“…5. Similar to the effects of a-CTLA-4 antibodies, the injection of 250 mg each of a-B7-1 and a-B7-2 antibodies, known to block the ligands for CTLA-4 and CD28 (20,21), resulted in higher average pmel-1 Each data point represents a cell, and the population mean is indicated by a black bar. Data are pooled from at least three independent experiments.…”

Section: Effects Of Other Antibodies On Pmel-1 Dynamics In Tdlnsmentioning

confidence: 96%

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Pentcheva-Hoang

Simpson

Montalvo-Ortiz

et al. 2014

Cancer Immunology Research

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It is now clear that anti-CTLA-4 (a-CTLA-4) antibodies stimulate tumor immunity either by relieving inhibition of effector T-cell function or by depletion of regulatory T cells (Treg). Several recent reports, however, have suggested that these antibodies may deliver a "go" signal to effector T cells, thus interrupting T-cell receptor signaling and subsequent T-cell activation. We examined the behavior of melanoma-specific CD8 þ pmel-1 T cells in the B16/BL6 mouse model using intravital microscopy. Pmel-1 velocities in progressively growing tumors were lower than their velocities in tumors given a therapeutic combination that included a-CTLA-4 antibodies, suggesting that successful immunotherapy correlates with greater T-cell motility. When a-CTLA-4 antibodies were injected during imaging, the velocities of pmel-1 T cells in tumor-draining lymph nodes also increased. Because a-CTLA-4 Fab fragments had the same effect as the intact antibody, the higher T-cell motility does not seem to be due to CTLA-4 inhibitory signaling but rather to the release of nonproductive stable interactions between tumor-infiltrating T cells and tumor targets or antigen-presenting cells subsequent to CTLA-4 blockade. This phenomenon resembles the recently described reversal of the antiviral T-cell motility paralysis by programmed death 1 (PD-1)-specific antibodies during T-cell exhaustion in persistent viral infections. Cancer Immunol Res; 2(10); 970-80. Ó2014 AACR.

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“…In addition, full activation of these cells requires the binding of costimulatory molecules expressed on one cell to costimulatory molecules expressed on the other (3,4). One such costimulatory molecule is CD86 (B7-2), which is expressed at a low level on a resting B cell (5,6), but is up-regulated following the stimulation of BCR (7,8), CD40 (9,10), MHC class II (11), LPS receptor (5,7,12,13), IL-4R (14,15), and/or ␤ 2 -adrenergic receptor (␤ 2 AR) (16,17). CD86 binds to the costimulatory molecule CD28 on the Th cell to increase the expression of the costimulatory molecule CD40 ligand (CD40L) on the Th cell and also to increase the level of cytokine produced by the Th cell (13,15,18).…”

Section: Selective Regulation Of Mature Igg1 Transcription By Cd86mentioning

confidence: 99%

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

Podojil

Sanders

2003

The Journal of Immunology

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Stimulation of CD86 and the β2-adrenergic receptor (β2AR) on a B cell, either alone or together, is known to increase the level of IgG1 protein produced by a CD40 ligand/IL-4-activated B cell. It is also known that the mechanism by which CD40 and IL-4R stimulation on a B cell increases the level of IgG1 protein is by increasing germline γ1 transcription, IgG1 class switching, and mature IgG1 transcription, while the molecular mechanism responsible for mediating the CD86- and β2AR-induced effect remains unknown. In the present study using real-time PCR we show that the level of mature IgG1 transcription increases in CD40 ligand/IL-4-activated B cells following stimulation of either CD86 and/or β2AR, and that this increase reflects the increase in IgG1 protein. Furthermore, we show that the CD86- and/or β2AR-induced increase in mature IgG1 transcript is due to an increase in the rate of mature IgG1 transcription, as determined by nuclear run-on analysis. This effect is additive when both receptors are stimulated and is lost when B cells from CD86- and β2AR-deficient mice are used. In contrast, the level of germline γ1 transcription, the stability of mature IgG1 transcript, the number of IgG1-positive B cells, and the number of IgG1-secreting B cells did not change. These results provide the first evidence that CD86 and/or β2AR stimulation on a CD40 ligand/IL-4-activated B cell increases the level of IgG1 protein produced per cell by increasing the rate of mature IgG1 transcription.

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Identification of an Alternative CTLA-4 Ligand Costimulatory for T Cell Activation

Cited by 503 publications

References 14 publications

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naive CD4+ T cells

Cytotoxic T Lymphocyte Antigen-4 Blockade Enhances Antitumor Immunity by Stimulating Melanoma-Specific T-cell Motility

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

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