Effect of CD3δ Deficiency on Maturation of α/β and γ/δ T-Cell Lineages in Severe Combined Immunodeficiency

Dadi, Harjit; Simon, Amos J.; Roifman, Chaim M.

doi:10.1056/nejmoa031178

Cited by 187 publications

(146 citation statements)

References 30 publications

(20 reference statements)

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“…As noted previously, CD3␦ Ϫ/Ϫ mice are blocked in development at the DP thymocyte stage but preserve normal pre-TCR function (45,46). In contrast, CD3␦-deficient humans have an early developmental block at the level of the pre-TCR (47,48). CD3␥ Ϫ/Ϫ mice, in contrast, are blocked at the DN stage as noted above (27), while human CD3␥ deficiency leads to mild thymic alterations with development of both DP and SP thymocytes (49).…”

Section: Discussionmentioning

confidence: 72%

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Touma

Sun

Clayton

et al. 2007

The Journal of Immunology

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CD3εγ and CD3εδ are noncovalent heterodimers; each consists of Ig-like extracellular domains associated side-to-side via paired terminal β-strands that are linked to individual subunit membrane proximal stalk segments. CD3ε, CD3γ, and CD3δ stalks contain the RxCxxCxE motif. To investigate the functional importance of a CD3 stalk and terminal β-strand, we created a CD3γ double mutant CD3γC82S/C85S and a CD3γ β-strand triple mutant CD3γQ76S/Y78A/Y79A for use in retroviral transduction of lymphoid progenitors for comparison with CD3γwt. Although both mutant CD3γ molecules reduced association with CD3ε in CD3εγ heterodimers, CD3γQ76S/Y78A/Y79A abrogated surface TCR expression whereas CD3γC82S/C85S did not. Furthermore, CD3γC82S/C85S rescued thymic development in CD3γ−/− fetal thymic organ culture. However, the numbers of double-positive and single-positive thymocytes after CD3γC82S/C85S transduction were significantly reduced despite surface pre-TCR and TCR expression comparable to that of CD3γ−/− thymocytes transduced in fetal thymic organ culture with a retrovirus harboring CD3γwt cDNA. Furthermore, double-negative thymocyte development was perturbed with attenuated double-negative 3/double-negative 4 maturation and altered surface-expressed CD3εγ, as evidenced by the loss of reactivity with CD3γ N terminus-specific antisera. Single histidine substitution of either CD3γ stalk cysteine failed to restore CD3εγ association and conformation in transient COS-7 cell transfection studies. Thus, CD3γC82 and CD3γC85 residues likely are either reduced or form a tight intrachain disulfide loop rather than contribute to a metal coordination site in conjunction with CD3εC80 and CD3εC83. The implications of these results for CD3εγ and TCR structure and signaling function are discussed.

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Section: Discussionmentioning

confidence: 72%

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Touma

Sun

Clayton

et al. 2007

The Journal of Immunology

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“…Although the same authors showed that isolated ␣␤ and ␦⑀ dimers do not normally assemble into ␣␤(␦⑀) 2 complexes in vitro, intrathymic selection mechanisms may expand, in vivo, the otherwise rare T cell precursors that manage to assemble a viable surface TCR⅐CD3 complex with such stoichiometry. In vivo observations further support this contention, because human CD3␥-deficient individuals showed significant T cell development with only mild lymphopenia and immunodeficiency, whereas CD3␦-deficient patients had no T cells and very severe clinical abnormalities (35).…”

Section: Fig 6 Characterization Of the Rw2-8c8 Antibody A Purifiedmentioning

confidence: 79%

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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“…Microarray experiments may also provide insight into biological or pathogenetic mechanisms [8][9][10][11]. However, to our knowledge no microarray analyses in CVID have been reported.…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7– effector-memory T cells

Holm

Sivertsen

Tunheim

et al. 2004

Clinical and Experimental Immunology

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SUMMARYCommon variable immunodeficiency (CVID) represents a heterogeneous group of antibody deficiency syndromes, characterized by defective antibody production in which T cell deficiency may play a pathogenic role. A subgroup of CVID patients has impaired in vitro T cell proliferation. Using microarray analyses of T cells from these patients, we found a gene expression pattern different from healthy controls and patients with X-linked agammaglobulinaemia. The profile of the differentially expressed genes suggests enhanced cytotoxic effector functions, antigen experienced or chronically activated T cells and a predominance of CCR7 -T cells. Further experiments using flow cytometry revealed a striking predominance of CCR7 -T cells in a subgroup of CVID patients, and an association with impaired T cell proliferation. Our observations indicate that a predominance of CCR7 -T cells with effector-memory cell features and with reduced proliferative capacity may characterize a subgroup of CVID.

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Effect of CD3δ Deficiency on Maturation of α/β and γ/δ T-Cell Lineages in Severe Combined Immunodeficiency

Cited by 187 publications

References 30 publications

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

Importance of the CD3γ Ectodomain Terminal β-Strand and Membrane Proximal Stalk in Thymic Development and Receptor Assembly

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

Gene expression analysis of peripheral T cells in a subgroup of common variable immunodeficiency shows predominance of CCR7– effector-memory T cells

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