An in Vivo Functional Immune System Lacking Polyclonal T‐Cell Surface Expression of the CD3/Ti(WT31) Complex

Regueiro, José R.; López‐Botet, Miguel; Landázuri, Manuel O.; Alcamí, José; Corell, Alfredo; Martin-Villa, José Manuel; Jl, Vicario; Arnaiz‐Villena, Antonio

doi:10.1111/j.1365-3083.1987.tb02306.x

Cited by 20 publications

(14 citation statements)

References 19 publications

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“…1A, and Ref. 47). But they could be caused by the existence of undefined modifying genes in these individuals, as shown in other immunodeficiencies (48).…”

Section: Discussionmentioning

confidence: 99%

TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ

Torres

Alcover

Zapata

et al. 2003

The Journal of Immunology

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The contribution of CD3γ to the surface expression, internalization, and intracellular trafficking of the TCR/CD3 complex (TCR) has not been completely defined. However, CD3γ is believed to be crucial for constitutive as well as for phorbol ester-induced internalization. We have explored TCR dynamics in resting and stimulated mature T lymphocytes derived from two unrelated human congenital CD3γ-deficient (γ−) individuals. In contrast to γ− mutants of the human T cell line Jurkat, which were selected for their lack of membrane TCR and are therefore constitutively surface TCR negative, these natural γ− T cells constitutively expressed surface TCR, mainly through biosynthesis of new chains other than CD3γ. However, surface (but not intracellular) TCR expression in these cells was less than wild-type cells, and normal surface expression was clearly CD3γ-dependent, as it was restored by retroviral transduction of CD3γ. The reduced surface TCR expression was likely caused by an impaired assembly or membrane transport step during recycling, whereas constitutive internalization and degradation were apparently normal. Ab binding to the mutant TCR, but not phorbol ester treatment, caused its down-modulation from the cell surface, albeit at a slower rate than in normal controls. Kinetic confocal analysis indicated that early ligand-induced endocytosis was impaired. After its complete down-modulation, TCR re-expression was also delayed. The results suggest that CD3γ contributes to, but is not absolutely required for, the regulation of TCR trafficking in resting and Ag-stimulated mature T lymphocytes. The results also indicate that TCR internalization is regulated differently in each case.

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“…1A, and Ref. 47). But they could be caused by the existence of undefined modifying genes in these individuals, as shown in other immunodeficiencies (48).…”

Section: Discussionmentioning

confidence: 99%

TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ

Torres

Alcover

Zapata

et al. 2003

The Journal of Immunology

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“…Phytohaemagglutinin response was decreased (7% relative to control). Subsequent immunological evaluation is shown in table 1 5…”

Section: Case Reportmentioning

confidence: 99%

B cell non-Hodgkin's lymphoma in a girl with the DiGeorge anomaly

Ramos

López‐Laso

Ruiz–Contreras

et al. 1999

Archives of Disease in Childhood

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“…PBMCs were obtained from donors or immunodeficient patients by density gradient centrifugation using Ficoll-Hypaque (Lymphoprep; Nyegaard, Oslo, Norway) following standard procedures (24). Isolated cells (8 ϫ 10 4 ) were placed in round-bottom microtiter plates (Nunc, Roskilde, Denmark) in 170 l of AIM-V culture medium (Gibco BRL, Paisley, United Kingdom) supplemented with 1% penicillin-streptomycin (Difco) and 1% glutamine 20 mM (Whittaker, Walkersville, Md.).…”

Section: Subjectsmentioning

confidence: 99%

A Point Mutation in a Domain of Gamma Interferon Receptor 1 Provokes Severe Immunodeficiency

Allende¹,

López-Goyanes²,

Paz-Artal³

et al. 2001

Clin Diagn Lab Immunol

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Gamma interferon (IFN-␥) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-␥ receptor ligand-binding chain (IFN-␥R1) deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-␥R1 ligandbinding domain in a Spanish patient with mycobacterial disseminated infection and multifocal osteomyelitis is characterized. The mutation generates an amino acid change that does not abrogate protein expression on the cellular surface but that severely impairs responses after the binding of IFN-␥ (CD64 and HLA class II induction and tumor necrosis factor alpha and interleukin-12 production). A patient's younger brother, who was also probably homozygous for the mutation, died from meningitis due to Mycobacterium bovis. These findings suggest that a point mutation may be fatal when it affects functionally important domains of the receptor and that the severity is not directly related to a lack of IFN-␥ receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.Gamma interferon (IFN-␥) is a widely studied cytokine and one of the most promising biological agents, with great therapeutic potential for several pathologies. This is mainly due to its immunomodulatory and antiproliferative effects and, probably, to its antiviral capacity (13). IFN-␥, after binding to its highaffinity receptor, regulates over 200 genes (7). IFN-␥ upregulates major histocompatibility complex (MHC) class I protein expression and induces MHC class II proteins on a variety of leucocytes and epithelial cells. IFN-␥ is also the major cytokine responsible for activating or regulating the phagocytic function of mononuclear cells. It also regulates the production of several immunomodulatory or proinflammatory cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-␣) (7).The IFN-␥ high-affinity receptor is composed of at least two subunits. IFN-␥R1 (alpha chain or CD119) is the IFN-␥ binding chain. It is encoded by a 30-kb gene located on the long arm of chromosome 6 (23), and it is expressed at moderate levels on the surfaces of nearly all cells. IFN-␥R2 (beta chain or accessory factor 1) is the signaling chain (27), and it is encoded by a gene located on chromosome 21q22.1 (8).The relationship between IFN-␥, IL-12, and TNF-␣ makes up a particularly important system, since it controls mycobacterial infections in humans (14). Recently, several mutations in some components of this system (ligands or receptors) have been described (4,11,12,(17)(18)(19)21). Patients with these mutations have similar susceptibilities to infections by atypical and nontuberculous mycobacteria (5). MATERIALS AND METHODS Subjects.A 5-year-old Spanish girl from consanguineous parents was referred to our hospital with disseminated infecti...

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An in Vivo Functional Immune System Lacking Polyclonal T‐Cell Surface Expression of the CD3/Ti(WT31) Complex

Cited by 20 publications

References 19 publications

TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ

TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ

B cell non-Hodgkin's lymphoma in a girl with the DiGeorge anomaly

A Point Mutation in a Domain of Gamma Interferon Receptor 1 Provokes Severe Immunodeficiency

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