Primary Immunodeficiency Caused by Mutations in the Gene Encoding the CD3-γ Subunit of the T-Lymphocyte Receptor

Arnaiz‐Villena, Antonio; Timón, Marcos; Corell, Alfredo; Pérez-Aciego, Paloma; Martin-Villa, José Manuel; Regueiro, José R.

doi:10.1056/nejm199208203270805

Cited by 219 publications

(125 citation statements)

References 13 publications

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“…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). Consistent with these differences, a human CD3␦ transgene can support pre-TCR-mediated thymic progression (50,51).…”

Section: Discussionmentioning

confidence: 82%

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: 82%

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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“…Causative abnormalities are found in genes with intracellular (ADA, JAK3, ZAP70, RAG, and MHC) and extracellular expression (IL2RG, CD3E, and CD3G) (1)(2)(3)(4)(5)(6)(7)(8). Affected genes include those involved in cytokine pathways (2,3,6), Ag presentation (5), purine salvage (1), and Ag receptor rearrangement and signal transduction (7). The leukocyte common Ag CD45 is an abundant hemopoietic-specific transmembrane protein tyrosine phosphatase (9,10).…”

mentioning

confidence: 99%

A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Tchilian

Wallace

Wells

et al. 2001

The Journal of Immunology

160

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SCID is a heterogeneous group of hereditary diseases. Mutations in the common γ-chain (γc) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31–32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.

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“…In particular, it has been consistently shown that in the absence of CD3␥ or CD3␦, TCR⅐CD3 expression (or conformation) is more impaired in mature peripheral CD8 ϩ cells than in their CD4 ϩ counterparts, both in human and in murine deficiencies (3)(4)(5)(6)(7). Three other observations suggested the existence of CD8 ϩ cell-specific defects in human CD3␥ deficiency: first, the proband died after a viral infection (a cytolytic T-celldependent function) despite normal antibody responses (helper T-cell-dependent) (8); second, the peripheral blood CD8 ϩ T cell subset was more strongly reduced (5-fold) than the CD4 ϩ T cell subset (only 2-fold) (4); and third, the scanty peripheral CD3␥-deficient CD8 ϩ cells, but not CD4 ϩ cells, failed to grow in vitro under optimal stimuli (PHA and allogeneic feeder cells) (4). This paradox may be the reflection either of subset-specific defective maturation of CD3 low to CD3 high thymocytes in these mutants (3) or of hitherto unrecognized biochemical differences in the assembly or maturation of TCR⅐CD3 complexes between peripheral CD8 ϩ and CD4 ϩ T lymphocytes, revealed only when certain CD3 chains are absent.…”

mentioning

confidence: 99%

Conformational and Biochemical Differences in the TCR·CD3 Complex of CD8+ Versus CD4+ Mature Lymphocytes Revealed in the Absence of CD3γ

Zapata¹,

Pacheco‐Castro²,

Torres³

et al. 1999

Journal of Biological Chemistry

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Mature CD4؉ and CD8 ؉ T lymphocytes are believed to build and express essentially identical surface ␣␤ T-cell receptor-CD3 (TCR⅐CD3) complexes. However, TCR⅐CD3 expression has been shown to be more impaired in CD8 ؉ cells than in CD4؉ cells when CD3␥ is absent in humans or mice. We have addressed this paradox by performing a detailed phenotypical and biochemical analysis of the TCR⅐CD3 complex in human CD3␥-deficient CD8؉ and CD4 ؉ T cells. The results indicated that the membrane TCR⅐CD3 complex of CD8 ؉ T lymphocytes was conformationally different from that of CD4 ؉ lymphocytes in the absence of CD3␥. In addition, CD8؉ , but not CD4 ؉ , CD3␥-deficient T lymphocytes were shown to contain abnormally glycosylated TCR␤ proteins, together with a smaller, abnormal TCR chain (probably incompletely processed TCR␣). These results suggest the existence of hitherto unrecognized biochemical differences between mature CD4؉ and CD8 ؉ T lymphocytes in the intracellular control of ␣␤TCR⅐CD3 assembly, maturation, or transport that are revealed when CD3␥ is absent. Such lineage-specific differences may be important in receptor-coreceptor interactions during antigen recognition.Mature ␣␤ T lymphocytes recognize pathogen-derived peptides on antigen-presenting cells by means of the multimeric membrane protein ensemble termed the T-cell receptor (TCR) 1 ⅐CD3 complex. This TCR⅐CD3 complex includes two clonally distributed variable chains that directly interact with antigens (TCR␣ and TCR␤) and four invariant polypeptides that regulate assembly and signal transduction (CD3␥, CD3␦, CD3⑀, and ) (1). The assembly of complete TCR⅐CD3⅐ complexes takes place in a highly ordered manner within the endoplasmic reticulum: first CD3 chains, then TCR chains, and finally chains. Further conformational maturation, including carbohydrate processing, occurs in the Golgi apparatus before exportation of mature complexes to the T cell surface. The biochemical machinery involved in the assembly, processing, and exportation of TCR⅐CD3 complexes is assumed to be shared by all ␣␤ T-lineage cells. Thus, CD4ϩ and CD8 ϩ are believed to build biochemically and conformationally identical antigen receptors, although differences in the numbers that reach or remain at the cell surface have been noted (2). Therefore, the lack of any CD3 chain would be expected to affect to a similar extent the assembly and exportation of TCR⅐CD3 complexes by mature CD4 ϩ and CD8 ϩ T cells. However, this was not the case in several murine and human CD3 deficiencies (reviewed in Ref.3). In particular, it has been consistently shown that in the absence of CD3␥ or CD3␦, TCR⅐CD3 expression (or conformation) is more impaired in mature peripheral CD8 ϩ cells than in their CD4 ϩ counterparts, both in human and in murine deficiencies (3-7). Three other observations suggested the existence of CD8 ϩ cell-specific defects in human CD3␥ deficiency: first, the proband died after a viral infection (a cytolytic T-celldependent function) despite normal antibody responses (helper T-cell-dependent) (8...

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Primary Immunodeficiency Caused by Mutations in the Gene Encoding the CD3-γ Subunit of the T-Lymphocyte Receptor

Cited by 219 publications

References 13 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

A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID

Conformational and Biochemical Differences in the TCR·CD3 Complex of CD8+ Versus CD4+ Mature Lymphocytes Revealed in the Absence of CD3γ

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