A Native Soluble Form of CTLA-4

Oaks, Martin K.; Hallett, Karen M.; Penwell, R T; Stauber, E C; Warren, S J; Tector, A. Joseph

doi:10.1006/cimm.2000.1649

Cited by 221 publications

(242 citation statements)

References 41 publications

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“…In addition, mutations in the amino acid sequence of the cytoplasmic tail of CTLA-4 can lead to its accumulation at the cell surface [50] although genetic studies have not indicated that mutations at this site predisposes to SLE. A soluble form of CLTA-4 has also been described, which is predominantly expressed on resting T-cells [51] and is increased in the serum of patients with SLE [52,53]. The soluble form of CLTA-4 lacks the transmembrane domain of the CTLA-4 gene implying that alterations in its expression are not secondary to changes in the recycling of membrane CTLA-4.…”

Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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“…A sCTLA-4, namely a functional molecule with specific CD80 and CD86 binding ability, generated by alternatively spliced mRNA has been described [10,13,20,[49][50][51][52][53]. The mRNA encoding sCTLA-4 consists of three exons: exon 1 encoding the leader peptide, exon 2 the ligand-binding domain, and exon 4 the cytoplasmic tail, but it lacks exon 3 encoding the transmembrane domain [10,20,53].…”

Section: Soluble Form Of Ctla-4mentioning

confidence: 99%

“…The mRNA encoding sCTLA-4 consists of three exons: exon 1 encoding the leader peptide, exon 2 the ligand-binding domain, and exon 4 the cytoplasmic tail, but it lacks exon 3 encoding the transmembrane domain [10,20,53]. The spliced transcript produces a 23-kDa sCTLA-4 characterized by a cytoplasmic tail shorter than that of the full-length form of the CTLA-4 antigen.…”

Section: Soluble Form Of Ctla-4mentioning

confidence: 99%

“…In addition, sCTLA-4 contains the MYPPPY motif located in the extracellular domain which is critical for B7 molecule binding [23]. Therefore it maintains the ability to bind CD80/CD86 and to participate in the B7/CTLA-4/CD28 signalling pathway of T-cell regulation [10,20,53]. Soluble CTLA-4 transcripts have been detected in lymph nodes, spleen, CD4 and CD8 subsets of T cells, B lymphocytes [10], and in monocytes [8,56], but not in a wide variety of nonlymphoid tissues.…”

Section: Soluble Form Of Ctla-4mentioning

confidence: 99%

“…A native soluble form of CTLA-4 (sCTLA-4) has been described [10]. The presence of high serum concentrations of sCTLA-4 is correlated with several autoimmune diseases [11].…”

Section: Introductionmentioning

confidence: 99%

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The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Saverino

Simone

Bagnasco

et al. 2010

Autoimmun Highlights

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CTLA-4, initially described as a membranebound molecule, is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence shows the CTLA-4 gene to be an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T-lymphocyte-associated antigen-4 (sCTLA-4) has been established and shown to possess CD80/CD86 binding activity and in vitro immunoregulatory functions. sCTLA-4 is generated by alternatively spliced mRNA. Whereas low levels of sCTLA-4 are detected in normal human serum, increased serum levels are observed in several autoimmune diseases (e.g. Graves’ disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, coeliac disease, autoimmune pancreatitis and primary biliary cirrhosis). The biological significance of increased sCTLA-4 serum levels is not fully clarified yet. On the one hand, it can be envisaged that sCTLA-4 specifically inhibits early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete for the binding of the membrane form of CTLA-4 with CD80/CD86 in the later phases of T-lymphocyte activation, causing a reduction in inhibitory signalling. This double-edged nature of sCTLA-4 to block the binding of CD28 to CD80/CD86 may result in different outcomes during the clinical course of an autoimmune disease.

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Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

2019

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Background With the recent advances in the understanding of the interaction of the immune system with developing tumor, it has become imperative to consider the immunological parameters for both cancer diagnosis and disease prognosis. Additionally, in the era of emerging immunotherapeutic strategies in cancer, it is very important to follow the treatment outcome and also to predict the correct immunotherapeutic strategy in individual patients. There being enormous heterogeneity among tumors at different sites or between primary and metastatic tumors in the same individual, or interpatient heterogeneity, it is very important to study the tumor‐immune interaction in the tumor microenvironment and beyond. Importantly, molecular tools and markers identified for such studies must be suitable for monitoring in a noninvasive manner. Recent findings Recent studies have shown that the immune checkpoint molecules play a key role in the development and progression of tumors. In‐depth studies of these molecules have led to the development of most of the cancer immunotherapeutic reagents that are currently either in clinical use or under different phases of clinical trials. Interestingly, many of these cell surface molecules undergo alternative splicing to produce soluble isoforms, which can be tracked in the serum of patients. Conclusions Several studies demonstrate that the serum levels of these soluble isoforms could be used as noninvasive markers for cancer diagnosis and disease prognosis or to predict patient response to specific therapeutic strategies.

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A Native Soluble Form of CTLA-4

Cited by 221 publications

References 41 publications

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

The soluble CTLA-4 receptor and its role in autoimmune diseases: an update

Soluble immune checkpoint molecules: Serum markers for cancer diagnosis and prognosis

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