Lymphoproliferation in CTLA-4–Deficient Mice Is Mediated by Costimulation-Dependent Activation of CD4 + T Cells

Chambers, Cynthia A.; Sullivan, Timothy J.; Allison, James P.

doi:10.1016/s1074-7613(00)80406-9

Cited by 373 publications

(274 citation statements)

References 61 publications

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“…Of note, we could also clearly observe negative regulation of Agspecific, preactivated CD8 ϩ T cells following CTLA-4/TCR coengagement using the 2C T cells. Thus, although recent studies have shown that CLTA-4 may not exert significant effects during primary CD8 ϩ T cell activation (52,65), our results and those of others (53,54) suggest that CTLA-4-mediated negative regulation of CD8 ϩ T cells may occur both indirectly, through inhibition of CD4 ϩ helper functions, and directly, through inhibition of expansion and cytokine production during secondary Ag encounters.…”

Section: Discussioncontrasting

confidence: 68%

Blockade of T Cell Activation Using a Surface-Linked Single-Chain Antibody to CTLA-4 (CD152)

Griffin

Hong

Holman

et al. 2000

The Journal of Immunology

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CTLA-4 (CD152) engagement can down-regulate T cell activation and promote the induction of immune tolerance. However, the strategy of attenuating T cell activation by engaging CTLA-4 has been limited by sharing of its natural ligands with the costimulatory protein CD28. In the present study, a CTLA-4-specific single-chain Ab (scFv) was developed and expressed on the cell surface to promote selective engagement of this regulatory molecule. Transfectants expressing anti-CTLA-4 scFv at their surface bound soluble CTLA-4 but not soluble CD28. Coexpression of anti-CTLA-4 scFv with anti-CD3ε and anti-CD28 scFvs on artificial APCs reduced the proliferation and IL-2 production by resting and preactivated bulk T cells as well as CD4+ and CD8+ T cell subsets. Importantly, expression of anti-CTLA-4 scFv on the same cell surface as the TCR ligand was essential for the inhibitory effects of CTLA-4-specific ligation. CTLA-4-mediated inhibition of tyrosine phosphorylation of components of the proximal TCR signaling apparatus was similarly dependent on coexpression of TCR and CTLA-4 ligands on the same surface. These findings support a predominant role for CTLA-4 function in the modification of the proximal TCR signal. Using T cells from DO11.10 and 2C TCR transgenic mice, negative regulatory effects of selective CTLA-4 ligation were also demonstrated during the stimulation of Ag-specific CD4+ and CD8+ T cells by MHC/peptide complexes. Together these studies demonstrate that selective ligation of CTLA-4 using a membrane-bound scFv results in attenuated T cell responses only when coengaged with the TCR during T cell/APC interaction and define an approach to harnessing the immunomodulatory potential of CTLA-4-specific ligation.

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Section: Discussioncontrasting

confidence: 68%

Blockade of T Cell Activation Using a Surface-Linked Single-Chain Antibody to CTLA-4 (CD152)

Griffin

Hong

Holman

et al. 2000

The Journal of Immunology

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“…The Frauwirth results are in keeping with those from Bachmann et al (27) who reported, while using a different CD8 ϩ TCR-transgenic mouse that CD152 played little, if any, role in regulating CD8 ϩ T cell responses. This contrasts with the in vivo observations for CD4 ϩ T cells (5,6), and with the fact that the predominant cell type that accumulates in the CD152 KO mouse is CD4 ϩ (28).…”

Section: Discussioncontrasting

confidence: 63%

CD152 Ligation by CD80 on T Cells Is Required for the Induction of Unresponsiveness by Costimulation-Deficient Antigen Presentation

Chai

Vendetti

Amofah

et al. 2000

The Journal of Immunology

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Two apparently contradictory observations have been made concerning peripheral T cell tolerance; costimulation-deficient Ag presentation leads to unresponsiveness, and CTLA4 (CD152) ligation is required for unresponsiveness to be induced. This issue was addressed using a CD80− CD86low B cell line to present Ag to DO.11.10 naive CD4+ T cells. Proliferation was substantially enhanced by anti-CD80 or anti-CD152, but was inhibited by anti-CD86. Furthermore, anti-CD80 partially, and anti-CD152 totally protected cloned DO.11.10 T cells from the induction of unresponsiveness following culture with peptide and Chinese hamster ovary H2-Ad+ CD80− CD86− cells. Fab of anti-CD80 caused similar enhancement, and coimmobilized anti-CD80 failed to costimulate the anti-CD3 response of purified T cells, indicating that direct signaling by anti-CD80 was not responsible for these effects. The possibility that anti-CD80 liberated CD28 molecules that were sequestered by the T cell-expressed CD80, enabling them to coaggregate with TCR:CD3 complexes was excluded by finding that anti-CD80 and anti-CD152 individually caused maximal enhancement, rather than having additive effects. These data suggest that T cell-expressed CD80 has a regulatory function and plays a key role in the induction of unresponsiveness due to costimulation-deficient Ag presentation by the ligation of CD152 on neighboring, or even the same, T cell.

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“…CTLA-4-deficient mice develop more severe and systemic autoimmune diseases with early onset [13][14][15], whereas PD-1-deficient mice develop milder and organspecific autoimmune diseases with late onset [8,12]. These results suggest a minor impact of PD-1-mediated regulation in general lymphoid organs and a possible role for PD-1 in regulating immune responses in specific organs.…”

Section: Discussionmentioning

confidence: 87%

“…PD-1 is expressed on a subpopulation of thymocytes and on both T and B cells after antigenic stimulation [6, 10,11]. Although PD-1-deficient mice develop autoimmune diseases, such as lupus-like glomerulonephritis and dilated cardiomyopathy [8,12], these mice display markedly different phenotypes as compared with CTLA-4-deficient mice [13][14][15], suggesting a role for PD-1 distinct from that for CTLA-4. Two B7 family molecules have been identified as the ligands for PD-1: B7-H1/PD-L1 [16,17] (hereafter referred to as B7-H1) and B7-DC/PD-L2 [18,19] (hereafter referred to as B7-DC).…”

Section: Introductionmentioning

confidence: 99%

Preferential contribution of B7‐H1 to programmed death‐1‐mediated regulation of hapten‐specific allergic inflammatory responses

et al. 2003

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Programmed death-1 (PD-1) and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, are new CD28-B7 family members that may be involved in the regulation of immune responses. We examined the roles of these molecules in mouse hapten-induced contact hypersensitivity (CH). Administration of anti-PD-1 mAb at sensitization significantly enhanced and prolonged ear swelling. Treatment with anti-B7-H1 mAb, but not anti-B7-DC mAb, also enhanced CH reactions. The anti-PD-1 mAb treatment at sensitization significantly increased the T cell number of draining lymph nodes (DLN). B7-H1 was induced on activated T cells and antigen-presenting cells (APC) in the skin and the DLN, whereas B7-DC expression was restricted to dendritic cells (DC) in the dermis and the DLN. A particular subset of DC, B7-H1 + B7-DC -CD86 low , was found in sensitized DLN. The blockade of B7-H1, but not B7-DC, dramatically enhanced the initial T cell proliferative responses against hapten-pulsed DLN APC, suggesting the preferential contribution of B7-H1 to the T cell-APC interaction. Our results demonstrate the regulatory role of PD-1 and the differential roles of B7-H1 and B7-DC in hapten-induced immune responses. The PD-1-B7-H1 pathway may play a unique role in regulating inflammatory responses.

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Lymphoproliferation in CTLA-4–Deficient Mice Is Mediated by Costimulation-Dependent Activation of CD4 + T Cells

Cited by 373 publications

References 61 publications

Blockade of T Cell Activation Using a Surface-Linked Single-Chain Antibody to CTLA-4 (CD152)

Blockade of T Cell Activation Using a Surface-Linked Single-Chain Antibody to CTLA-4 (CD152)

CD152 Ligation by CD80 on T Cells Is Required for the Induction of Unresponsiveness by Costimulation-Deficient Antigen Presentation

Preferential contribution of B7‐H1 to programmed death‐1‐mediated regulation of hapten‐specific allergic inflammatory responses

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