Cutting Edge: Transplantation Tolerance through Enhanced CTLA-4 Expression

Ariyan, Charlotte E.; Salvalaggio, Paolo R.O.; Fecteau, Scott; Deng, Songyan; Rogozinski, Linda; Mandelbrot, Didier A.; Sharpe, Arlene H.; Sayegh, Mohamed H.; Basadonna, Giacomo; Rothstein, David M.

doi:10.4049/jimmunol.171.11.5673

Cited by 72 publications

(60 citation statements)

References 22 publications

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“…The role of altered CD45 isoform expression in this setting is unclear. Although the isoform shift can occur in the absence of augmented CTLA-4 expression, the converse has not been demonstrated (19,20). Moreover, the shift in CD45 isoforms is not sufficient to enhance allograft survival in the absence of enhanced CTLA-4 expression.…”

Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 87%

“…3A) (20). Nonetheless, this phenotypic change is of key importance, because induction of CTLA-4 expression is essential for anti-CD45RB activity (19,20). Despite three doses, anti-CD45RB treatment mAb was no longer detectable in the serum or on the surface of splenocytes by day 7 (Fig.…”

Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 99%

“…3A) (20). Nonetheless, this phenotypic change is of key importance, because induction of CTLA-4 expression is essential for anti-CD45RB activity (19,20).…”

Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 99%

“…This occurs without depletion or overt T cell activation. Importantly, multiple lines of evidence indicate that CTLA-4 induction plays a specific and essential role in anti-CD45RB activity (19,20). These include the loss of tolerogenic activity: when anti-CD45RB is combined with anti-CTLA-4 or CTLA4-Ig (which interfere with CTLA-4:B7 interaction), when anti-CD45RB is combined with cyclosporin A (which prevents CTLA-4 up-regulation), or when anti-CD45RB is used in CTLA-4-deficient recipients (19,20).…”

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confidence: 99%

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Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Salvalaggio¹,

Camirand

Ariyan³

et al. 2006

The Journal of Immunology

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The role of CTLA-4 in tolerance is primarily inferred from knockout and blocking studies. Anti-CD45RB mediates allograft tolerance in mice by inducing CTLA-4 expression on CD4 cells, providing a novel opportunity to determine how therapeutic enhancement of CTLA-4 promotes tolerance. We now show that induced CTLA-4 expression normally resolves by day 17. Although thymectomy prolongs enhanced CTLA-4 expression, long-term engraftment is unaffected. To address the temporal relationship between increased CTLA-4 expression and engraftment, transplantation was delayed for various times after anti-CD45RB treatment. Delaying transplantation for 7 days (when CTLA-4 expression had peaked but treatment mAb was no longer detectable), resulted in long-term engraftment comparable to transplantation with no delay (day 0). Delaying transplantation from 10 to 18 days led to a progressively poorer outcome as CTLA-4 expression returned to baseline. This suggested that Ag exposure while CTLA-4 expression is enhanced is sufficient to induce long-term engraftment. To substantiate this, on day 0, anti-CD45RB-treated mice received BALB/c vs unrelated alloantigen, followed by transplantation of BALB/c islets 10 days later. Whereas recipients exposed to unrelated Ag experienced acute rejection, recipients exposed to donor Ag achieved long-term engraftment. Anti-CD45RB-treated mice exposed to alloantigen exhibited anergic CD4+CD25− effector cells and regulatory CD4+CD25+ cells. Moreover, CD25 depletion in the peritransplant period prevented anti-CD45RB-mediated engraftment. Thus, exposure of CD4 cells expressing CTLA-4 to donor Ag is necessary and sufficient to induce long-term engraftment which appears to be mediated by both regulation and anergy.

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Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 87%

Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 99%

“…3A) (20). Nonetheless, this phenotypic change is of key importance, because induction of CTLA-4 expression is essential for anti-CD45RB activity (19,20).…”

Section: Redosing Anti-cd45rb Does Not Improve Long-term Graft Acceptmentioning

confidence: 99%

mentioning

confidence: 99%

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Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Salvalaggio¹,

Camirand

Ariyan³

et al. 2006

The Journal of Immunology

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“…It has been demonstrated before that CTLA-4 up-regulation results in the promotion of allograft survival in transplantation studies (42). Because soluble MR fragments such as the ones used in this study induce up-regulation of CTLA-4, injection with such fragments could be a tempting approach to reduce immune responses in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

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Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjögren's syndrome

Downie-Doyle

Bayat

Rischmueller

et al. 2006

Arthritis & Rheumatism

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Objective. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of the T cell immune response, and the CTLA4 gene is highly polymorphic. Many positive associations between CTLA4 single-nucleotide polymorphisms (SNPs) and various autoimmune diseases have been identified. Two CTLA4 SNPs that are important relative to genetic susceptibility in human autoimmune diseases are the ؉49GA polymorphism in exon 1 and the CT60A/G polymorphism in the 3-untranslated region. Using these 2 polymorphisms as markers, we investigated possible genetic associations of CTLA4 in Australian patients with primary Sjögren's syndrome.Methods. One hundred eleven Australian Caucasian patients with primary SS and 156 population-based controls were genotyped for CTLA4 by polymerase chain reaction-restriction fragment length polymorphism methods, using the restriction enzymes BseXI (؉49G/A) and HpyCh4 IV (CT60).Results. The CT60 and ؉49G/A SNPs were in strong linkage disequilibrium, and only 3 haplotypes were observed. Significant differences in the haplotype frequencies between patients with primary SS and controls (P ‫؍‬ 0.032) were observed, with susceptibility to primary SS associated with both the ؉49A;CT60A haplotype and the ؉49A;CT60G haplotype, whereas the ؉49G;CT60G haplotype was protective against primary SS. The ؉49A;CT60G haplotype association was predominantly with Ro/La autoantibody-positive primary SS, and the dose of this haplotype influenced the severity of daytime sleepiness (P ‫؍‬ 0.036). The ؉49A; CT60A haplotype appeared to be protective against the development of Raynaud's phenomenon in patients with primary SS (odds ratio 0.49, 95% confidence interval 0.27-0.91).Conclusion. The CTLA4 ؉49G/A and CT60 haplotypes are associated with susceptibility to primary SS and with some extraglandular manifestations of the disease.

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Cutting Edge: Transplantation Tolerance through Enhanced CTLA-4 Expression

Cited by 72 publications

References 22 publications

Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjögren's syndrome

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