TCR Dynamics in Human Mature T Lymphocytes Lacking CD3γ

Torres, Pilar S.; Alcover, Andrés; Zapata, David A.; Arnaud, Jacques; Pacheco, Alberto; Martín-Fernández, José María; Villasevil, Eugenia M.; Sanal, Özden; Regueiro, José R.

doi:10.4049/jimmunol.170.12.5947

Cited by 25 publications

(19 citation statements)

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“…For fluorescence experiments, primary fibroblasts were activated at a density of 75,000 cells/ml in glass tissue culture slides (BD Falcon). HTLV-1 T cell lines were obtained from patients and normal donors as previously described (43). HTLV-1 T cells were cultured in RPMI medium supplemented with 10% FCS and 100 U/ml recombinant IL-2.…”

Section: Methodsmentioning

confidence: 99%

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

Torres¹,

Martı́nez-Barricarte²,

García-Gómez³

et al. 2014

J. Clin. Invest.

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Heterotrimers composed of B cell CLL/lymphoma 10 (BCL10), mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and caspase recruitment domain-containing (CARD) family adaptors play a role in NF-κB activation and have been shown to be involved in both the innate and the adaptive arms of immunity in murine models. Moreover, individuals with inherited defects of MALT1, CARD9, and CARD11 present with immunological and clinical phenotypes. Here, we characterized a case of autosomal-recessive, complete BCL10 deficiency in a child with a broad immunodeficiency, including defects of both hematopoietic and nonhematopoietic immunity. The patient died at 3 years of age and was homozygous for a loss-of-expression, loss-of-function BCL10 mutation. The effect of BCL10 deficiency was dependent on the signaling pathway, and, for some pathways, the cell type affected. Despite the noted similarities to BCL10 deficiency in mice, including a deficient adaptive immune response, human BCL10 deficiency in this patient resulted in a number of specific features within cell populations. Treatment of the patient's myeloid cells with a variety of pathogen-associated molecular pattern molecules (PAMPs) elicited a normal response; however, NF-κB-mediated fibroblast functions were dramatically impaired. The results of this study indicate that inherited BCL10 deficiency should be considered in patients with combined immunodeficiency with B cell, T cell, and fibroblast defects.

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Section: Methodsmentioning

confidence: 99%

Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity

Torres¹,

Martı́nez-Barricarte²,

García-Gómez³

et al. 2014

J. Clin. Invest.

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“…Cells-Herpesvirus saimiri-transformed T cell lines were derived with informed consent from the peripheral blood lymphocytes (PBLs) of a healthy congenital CD3␥-deficient (␥ Ϫ ) individual or the PBLs of normal donors (␥ ϩ ) as described previously (7,8). The T cell lines used in the experiments (DSF4, CD4 ϩ ␥ Ϫ ; CTRCD4, CD4 ϩ ␥ ϩ ; DSF8, CD8 ϩ ␥ Ϫ ; and CTO, CD8 ϩ ␥ ϩ ) had been cultured for 6 -7 years when the experiments were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Endo-␤-N-acetylglucosaminidase H and N-glycosidase F (Roche Applied Science) treatments were done as described (6,7). Finally, samples were resuspended in Laemmli sample buffer and boiled for 5 min before a short spin at 12,000 ϫ g. SDS-PAGE was performed on 10% polyacrylamide gels and analyzed by autoradiography.…”

Section: Methodsmentioning

confidence: 99%

Biochemical Differences in the αβ T Cell Receptor·CD3 Surface Complex between CD8+ and CD4+ Human Mature T Lymphocytes

Zapata

Schamel

Torres

et al. 2004

Journal of Biological Chemistry

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We have reported the existence of biochemical and conformational differences in the ␣␤ T cell receptor (TCR) complex between CD4 ؉ and CD8 ؉ CD3␥-deficient (␥ ؊ ) mature T cells. In the present study, we have furthered our understanding and extended the observations to primary T lymphocytes from normal (␥ ؉ ) individuals. Surface TCR⅐CD3 components from CD4 ؉ ␥ ؊ T cells, other than CD3␥, were detectable and similar in size to CD4 ؉ ␥ ؉ controls. Their native TCR⅐CD3 complex was also similar to CD4 ؉ ␥ ؉ controls, except for an ␣␤(␦⑀) 2 2 instead of an ␣␤␥⑀␦⑀ 2 stoichiometry. In contrast, the surface TCR␣, TCR␤, and CD3␦ chains of CD8 ؉ ␥ ؊ T cells did not possess their usual sizes. Using confocal immunofluorescence, TCR␣ was hardly detectable in CD8 ؉ ␥ ؊ T cells. Blue native gels (BN-PAGE) demonstrated the existence of a heterogeneous population of TCR⅐CD3 in these cells. Using primary peripheral blood T lymphocytes from normal (␥ ؉ ) donors, we performed a broad epitopic scan. In contrast to all other TCR⅐CD3-specific monoclonal antibodies, RW2-8C8 stained CD8 ؉ better than it did CD4 ؉ T cells, and the difference was dependent on glycosylation of the TCR⅐CD3 complex but independent of T cell activation or differentiation. RW2-8C8 staining of CD8 ؉ T cells was shown to be more dependent on lipid raft integrity than that of CD4 ؉ T cells. Finally, immunoprecipitation studies on purified primary CD4 ؉ and CD8 ؉ T cells revealed the existence of TCR glycosylation differences between the two. Collectively, these results are consistent with the existence of conformational or topological lineage-specific differences in the TCR⅐CD3 from CD4 ؉ and CD8 ؉ wild type T cells. The differences may be relevant for cis interactions during antigen recognition and signal transduction.␣␤ T lymphocytes recognize peptide-major histocompatibility complex ligands by means of a multimeric protein complex termed the ␣␤ T cell receptor (TCR) 1 CD3 complex (TCR⅐CD3). This structure is composed of a variable ␣␤ TCR dimer that binds antigens and three invariant dimers (CD3␥⑀, ␦⑀, and ) that are in charge of TCR⅐CD3 complex transport, stabilization, and signal transduction (1). The minimum stoichiometry, therefore, is believed to be ␣␤␥⑀␦⑀ 2 .Mature CD4 ϩ and CD8 ϩ ␣␤ T cells differ sharply in their major histocompatibility complex ligands, but their TCR⅐CD3 complex is believed to be qualitatively identical. The reduced ␣␤ TCR⅐CD3 staining levels observed in CD8 ϩ T cells, relative to CD4 ϩ T cells, were therefore reported as quantitative under this assumption (2). Unexpectedly, peripheral blood ␣␤ TCR⅐CD3 expression was shown to be more impaired in CD8 ϩ than in CD4 ϩ cells when CD3␥ (3, 4) or CD3␦ (5) was absent. These observations were followed by the description of conformational and biochemical differences in the TCR⅐CD3 complex between CD8 ϩ and CD4 ϩ CD3␥ deficient (␥ Ϫ ) T lymphocytes (6). Biosynthetic studies showed that CD8 ϩ but not CD4 ϩ ␥ Ϫ T cells lacked normal TCR␣. Instead, the CD4 ϩ ␥ Ϫ T cells contained a small ␣␤ hetero...

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“…Le phénotype modéré du déficit immunitaire de ces patients contraste avec le blocage au stade thymocyte « double néga-tif », secondaire au défaut de transduction de signal par le pré-TCR observé chez la souris dont le gène CD3G a été invalidé (Figure 3). Chez la souris, il n'existe aucune possibilité d'expression d'un complexe TCR/CD3 en l'absence de CD3γ contrairement à l'homme [25]. Cela suggère que le remplacement de la chaîne CD3γ par la chaîne CD3δ qui corrige la fonction du complexe TCR/CD3 dans des cellules humaines [25], ne se fait pas chez la souris.…”

Section: Déficit De La Chaîne Cd3gunclassified

“…Chez la souris, il n'existe aucune possibilité d'expression d'un complexe TCR/CD3 en l'absence de CD3γ contrairement à l'homme [25]. Cela suggère que le remplacement de la chaîne CD3γ par la chaîne CD3δ qui corrige la fonction du complexe TCR/CD3 dans des cellules humaines [25], ne se fait pas chez la souris.…”

Section: Déficit De La Chaîne Cd3gunclassified