Prevention of Acute Allograft Rejection by Antibody Targeting of TIRC7, a Novel T Cell Membrane Protein

Utku, Nalân; Heinemann, Thomas; Tullius, Stefan G.; Bulwin, Grit-Carsta; Beinke, Sören; Blumberg, Richard S.; Beato, Francisca; Randall, Jeffrey; Kojima, Ryoji; Busconi, Liliana; Robertson, Erle S.; Schülein, Ralf; Volk, Hans‐Dieter; Milford, Edgar L.; Gullans, Steven R.

doi:10.1016/s1074-7613(00)80634-2

Cited by 68 publications

(83 citation statements)

References 33 publications

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“…Indeed, whereas up to now, a role for the vacuolar proton pump a3 subunit in T cells has not been reported, the Tcirg1 gene encodes for another protein, TIRC7 (T-cell immune response cDNA-7) involved in T cell activation. 36 In the oc/oc mouse, the sequence encoding the TIRC7 protein is not affected by the oc mutation and TIRC7 is expressed in T lymphocytes (data not shown). However, a role of the a3 subunit in the secretion of INFg cannot be excluded.…”

Section: Altered Immunological Status In Oc/oc Micementioning

confidence: 92%

Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis

et al. 2004

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Infantile malignant osteopetrosis (IMO) is a rare and lethal disease characterized by an absence of bone resorption due to inactive OCLs. Affected patients display an increased bone mass and hematological defects. The osteopetrotic oc/oc mouse displays a bone phenotype similar to the one observed in IMO patients, and the same gene, Tcirg1, is mutated in this model and in the majority of these patients. Therefore, we explored in oc/oc mice the consequences of the perturbed bone microenvironment on hematopoiesis. We show that the myelomonocytic differentiation is increased, leading to an elevated number of OCLs and dendritic cells. B lymphopoiesis is blocked at the pro-B stage in the bone marrow of oc/oc mouse, leading to a low mature B-cell number. T-cell activation is also affected, with a reduction of IFNc secretion by splenic CD4 þ T cells. These alterations are associated with a low IL-7 expression in bone marrow. All these data indicate that the lack of bone resorption in oc/oc mice has important consequences in both myelopoiesis and lymphopoiesis, leading to a form of immunodeficiency. The oc/oc mouse is therefore an appropriate model to understand the hematological defects described in IMO patients, and to derive new therapeutic strategies.

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Section: Altered Immunological Status In Oc/oc Micementioning

confidence: 92%

Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis

et al. 2004

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“…The responder cells and stimulator cells were mixed in equal ratios in a total volume of 200 l at a cell concentration of 1 ϫ 10 6 cells/ml and cultivated in 96-well, round-bottom microtiter plates for 3 days at 37°C in 5% CO 2 . Subsequently, [ 3 H]thymidine (Amersham Pharmacia Biotech) was added 5 h before harvesting (38). Incorporation of [ 3 H]thymidine was assessed by scintillation using a 96-well plate reader (Packard Instrument, Meriden, CT).…”

Section: Mlr and Cell Proliferation Assaymentioning

confidence: 99%

“…Incorporation of [ 3 H]thymidine was assessed by scintillation using a 96-well plate reader (Packard Instrument, Meriden, CT). For cell proliferation assays, plate-bound anti-CD3-and anti-CD28-specific Abs were prepared according to a standard protocol, described previously (38), in either the presence or the absence of varying concentrations of the anti-mCEACAM1 a mAb CC1. Freshly prepared mouse T cells from spleen were incubated in 96-well, flat-bottom microtiter plates for 3 days at 37°C in 5% CO 2 .…”

Section: Mlr and Cell Proliferation Assaymentioning

confidence: 99%

Activation-Induced Expression of Carcinoembryonic Antigen-Cell Adhesion Molecule 1 Regulates Mouse T Lymphocyte Function

Nakajima¹,

Iijima²,

Neurath³

et al. 2002

The Journal of Immunology

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Carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) consists of highly related homologs in humans and rodents that are characterized by significant alternate splicing generating isoforms capable of negative intracellular signaling by virtue of two immunoreceptor tyrosine-based inhibition motifs in its cytoplasmic (cyt) tail. Although human T cells have been recently observed to express CEACAM1, the expression and function of CEACAM1 in mouse T cells have not been defined. Although resting mouse spleen T cells exhibited no evidence of CEACAM1 on the cell surface, CEACAM1 was rapidly up-regulated on CD4+ and CD8+ T cells after activation with either Con A or anti-CD3 without a requirement for either de novo transcription or translation due to the fact that CEACAM1 was present intracellularly before activation. Using a GST-CEACAM1-cytoplasmic tail fusion protein, it was shown that the cytoplasmic tail of CEACAM1 bound the src homology domain-containing phosphatase 1 and adaptor protein 1 complex in its phosphorylated and nonphosphorylated states, respectively. CEACAM1 ligation with an anti-CEACAM1 mAb resulted in inhibition of an allogeneic MLR and anti-CD3 plus anti-CD28 Ab-induced proliferation of spleen T cells in vitro and inhibition of a delayed-type hypersensitivity response to oxazolone in vivo. Inhibition of the delayed-type hypersensitivity response required that the anti-CEACAM1-specific mAb be present at the time of T cell sensitization. These studies support a role for CEACAM1 as a novel class of immunoreceptor tyrosine-based inhibition motif-bearing regulatory molecules on T cells that are active during early phases of the immune response in mice.

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“…Targeting of TIRC7 with specific Abs causes inhibition of Th1 cytokine secretion in human lymphocytes (12). In contrast, TIRC7-deficient mice show an enhanced T cell proliferation and Th1 cytokine secretion, suggesting a role for TIRC7 in regulating T cell response (43).…”

Section: Discussionmentioning

confidence: 99%

“…The membrane protein T cell immune response cDNA 7 (TIRC7) was identified in human T lymphocytes and was shown to play an important role in T cell activation (12). Tcirg1 (T cell immune regulator 1), the mouse gene encoding the homologous TIRC7, also encodes another protein, the a3 subunit of the vacuolar proton pump expressed in osteoclasts and necessary for bone resorption (13,14).…”

mentioning

confidence: 99%

Characterization of IL-10-Secreting T Cells Derived from Regulatory CD4+CD25+ Cells by the TIRC7 Surface Marker

Wakkach

Augier

Breittmayer

et al. 2008

The Journal of Immunology

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Natural CD25+CD4+ regulatory T cells (Treg) are essential for self-tolerance and for the control of T cell-mediated immune pathologies. However, the identification of Tregs in an ongoing immune response or in inflamed tissues remains elusive. Our experiments indicate that TIRC7, T cell immune response cDNA 7, a novel membrane molecule involved in the regulation of T lymphocyte activation, identifies two Treg subsets (CD25lowTIRC7+ and CD25highTIRC7−) that are characterized by the expression of Foxp3 and a suppressive activity in vitro and in vivo. We also showed that the CD25lowTIRC7+ subset represents IL-10-secreting Tregs in steady state, which is accumulated intratumorally in a tumor-bearing mice model. Blockade of the effect of IL-10 reversed the suppression imposed by the CD25lowTIRC7+ subset. Interestingly, these IL-10-secreting cells derived from the CD25highTIRC7− subset, both in vitro and in vivo, in response to tumoral Ags. Our present results strongly support the notion that, in the pool of natural Tregs, some cells can recognize foreign Ags and that this recognition is an essential step in their expansion and suppressive activity in vivo.

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Prevention of Acute Allograft Rejection by Antibody Targeting of TIRC7, a Novel T Cell Membrane Protein

Cited by 68 publications

References 33 publications

Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis

Hematological defects in the oc/oc mouse, a model of infantile malignant osteopetrosis

Activation-Induced Expression of Carcinoembryonic Antigen-Cell Adhesion Molecule 1 Regulates Mouse T Lymphocyte Function

Characterization of IL-10-Secreting T Cells Derived from Regulatory CD4+CD25+ Cells by the TIRC7 Surface Marker

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