Different composition of the human and the mouse γδ T cell receptor explains different phenotypes of CD3γ and CD3δ immunodeficiencies

Siegers, Gabrielle M.; Swamy, Mahima; Fernández-Malavé, Edgar; Minguet, Susana; Rathmann, Silvia; Guardo, Alberto C.; Pérez-Flores, V.; Regueiro, José R.; Alarcón, Balbino; Fisch, Paul; Schamel, Wolfgang W. A.

doi:10.1084/jem.20070782102207c

Cited by 16 publications

(15 citation statements)

References 28 publications

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“…Reconciling this to an obligate need for gdTCR signaling during differentiation, Chien and colleagues provided evidence for ligand-independent TCRgd signaling by spontaneous dimerization (Jensen et al, 2008). Murine TCRgd is certainly distinct from TCRab, by failure to associate with CD3d (Siegers et al, 2007), and by possession of residues analogous to those that mediate preTa dimerization (Jensen et al, 2008;Yamasaki et al, 2006). Dimerization offered a longsought explanation for ligand-independent, preTCR-mediated election of ab T cell progenitors (Hayday and Pennington, 2007).…”

Section: The Need For Focusmentioning

confidence: 95%

γδ T Cells and the Lymphoid Stress-Surveillance Response

2009

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The investigation of gammadelta T cells has identified a rapid lymphoid stress-surveillance response to microbial and nonmicrobial tissue perturbation. In addition to providing local protection, this response provides an immediate source of cytokines, chemokines, and other functions that can substantially affect downstream, adaptive immunity. Recent studies have identified striking mechanisms by which gammadelta cells meet the requirements of stress surveillance. For example, high response frequencies can reflect a unique nature of antigen engagement by the T cell receptor (TCR), developmental focusing of the repertoire by selection events, or the use of nonclonotypic receptors to initiate responses. Likewise, rapid functional deployment can be facilitated by the preprogramming of gammadelta cells during development. Additionally, gammadelta cells can directly influence adaptive immunity by functioning as antigen-presenting cells. With lymphoid stress surveillance likely to underpin numerous aspects of inflammation, tumor immunology, infectious disease, and autoimmunity, this perspective considers its properties and its emerging potential for clinical manipulation.

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Section: The Need For Focusmentioning

confidence: 95%

γδ T Cells and the Lymphoid Stress-Surveillance Response

2009

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“…3A), particularly sequences that are part of the A, B, C, E, F, and G ␤ strands responsible for the folding as a IgC domain, or the membrane-proximal CxxCxE motif that is involved in the pairing of CD3 with CD3␥ and ␦ chains [9,62], or with the TCR␣␤ heterodimer [63]. In fact, this conservation is possibly responsible for the ability of human CD3 chains to structurally and functionally substitute for mouse CD3 [46,64], or of human CD3␦ to associate with mouse CD3 [65]. Yet, some important differences between the extracellular sequences of CD3 from these two species can be observed.…”

Section: Comparison Of Cd3 Chain Sequences From Human Mouse and Othementioning

confidence: 97%

N-terminal negatively charged residues in CD3ɛ chains as a phylogenetically conserved trait potentially yielding isoforms with different isoelectric points: Analysis of human CD3ɛ chains

et al. 2009

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CD3varepsilon chains are essential to the structure, expression and signaling of T cell receptors. Here, we extend to human CD3varepsilon our previous data in mouse CD3varepsilon showing that, in T cells, proteolytic processing of the acidic N-terminal sequence of CD3varepsilon chains generate distinct polypeptide species that can be identified by two-dimension (IEF-SDS PAGE) electrophoresis and immunoblot. This was shown first by showing the processing of a fusion protein of GFP and the extracellular domain of mouse CD3varepsilon (mCD3GFP) expressed in Jurkat cells. Secondly, pI heterogeneity was also found in human CD3varepsilon chains immunoprecipitated from the surface of Jurkat cells or PHA blasts of human blood T lymphocytes. Comparison of CD3varepsilon chains from 27 different species shows that their N-terminal sequences share a strong acidic nature, despite the large differences in terms of length and composition, even among closely related species. Our results suggest that generation of CD3varepsilon chain isoforms with different N-terminal sequence and pI is a general phenomenon. Thus, as previously observed in the mouse, the relative abundance of CD3varepsilon chain species might regulate TCR/CD3 structure and function, including the strength of the interactions between CD3 dimers and the TCR clonotypic receptors, as well as TCR/CD3 activation thresholds. Interestingly, CD3varepsilon chains from 7 out of 27 species studied have putative N-glycosylation (NxS or NxT) motifs in their Ig extracellular domain. Their location, plus the conservation of residues involved in domain organization, the interactions with other CD3 chains, or the TCR, and signal triggering add new data useful to establish a permissive topology for the interaction between CD3 dimers and the TCR chains.

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“…In the United States, most cases of B-positive, NK-positive SCID occur as a result of IL7R (IL-7Ra) deficiency. 9,24 Rarer defects in components of the T-cell receptor have also been reported to cause SCID, including mutations in CD3D, [25][26][27][28] CD3E, 26 and CD247, 29,30 which encode the CD3 d, ε, and z chains, respectively. Defects in CD3G 31, 32 have not yet been observed to cause true SCID.…”

Section: B-positive Natural Killer-positive Severe Combined Immunodementioning

confidence: 99%