A Redundant Role of the CD3γ-Immunoreceptor Tyrosine-Based Activation Motif in Mature T Cell Function

Haks, Mariëlle C.; Cordaro, Tanina A.; Brakel, Jeroen H. N. van den; Haanen, John B.A.G.; Vries, E. F. R. De; Borst, Jannie; Krimpenfort, Paul; Kruisbeek, Ada M.

doi:10.4049/jimmunol.166.4.2576

Cited by 34 publications

(39 citation statements)

References 71 publications

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“…Also, TCR:CD8␣ interactions were studied in primary human T cells by FRET and revealed no differences between TCR␣␤: and TCR␣␤ (data not shown). In fact, these findings extend earlier observations that T cells are operational in the absence of CD3 components and/or their phosphorylation motifs (53,54). Current research aims at reintroduction of those TCR domains into the TCR␣␤: format that are responsible for association with endogenous CD3 components in an effort to generate a modified TCR that shows an improved functional versatility as well as an ability to down-regulate the expression of endogenous TCR and thereby limiting, at least theoretically, the self-reactivity of ignorant T cells (those T cells that have escaped mechanisms of tolerance).…”

Section: Discussionsupporting

confidence: 90%

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

Sebestyén¹,

Schooten²,

Sals³

et al. 2008

The Journal of Immunology

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TCR gene therapy is adversely affected by newly formed TCRαβ heterodimers comprising exogenous and endogenous TCR chains that dilute expression of transgenic TCRαβ dimers and are potentially self-reactive. We have addressed TCR mispairing by using a modified two-chain TCR that encompasses total human CD3ζ with specificities for three different Ags. Transfer of either TCRα:CD3ζ or β:CD3ζ genes alone does not result in surface expression, whereas transfer of both modified TCR chains results in high surface expression, binding of peptide-MHC complexes and Ag-specific T cell functions. Genetic introduction of TCRαβ:ζ does not compromise surface expression and functions of an endogenous TCRαβ. Flow cytometry fluorescence resonance energy transfer and biochemical analyses demonstrate that TCRαβ:CD3ζ is the first strategy that results in highly preferred pairing between CD3ζ-modified TCRα and β chains as well as absence of TCR mispairing between TCR:CD3ζ and nonmodified TCR chains. Intracellular assembly and surface expression of TCR:CD3ζ chains is independent of endogenous CD3γ, δ, and ε. Taken together, our data support the use of TCRαβ:CD3ζ to prevent TCR mispairing, which may provide an adequate strategy to enhance efficacy and safety of TCR gene transfer.

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Section: Discussionsupporting

confidence: 90%

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

Sebestyén¹,

Schooten²,

Sals³

et al. 2008

The Journal of Immunology

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“…While the CD3g chains are essential for both ab and gd T-cell development, only ab-T cells need CD3d chains for their maturation. Whereas the surface expression of TCRab and TCRgd are severely reduced in CD3g-deficient mice [30], normal proportions of ab-and gd-T cells are found in immunoreceptor tyrosine-based activation motif (ITAM)-deleted CD3g mice [43]. In contrast, while the surface expression of TCRab is severely reduced in CD3d-deficient mice, the surface expression of TCRgd is not much altered in such mice [33].…”

Section: Discussionmentioning

confidence: 99%

On the Role of CD3δ Chains in TCRγδ/CD3 Complexes during Assembly and Membrane Expression

et al. 2001

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The present study was performed in order to analyze whether T‐cell receptor (TCR)/CD3 assembly, intracellular transport and surface expression are carried in a similar way in αβ‐and γδ‐T cells. By means of optimal immunoprecipitation conditions with 35S‐methionine/cysteine‐ or biotin‐labelled TCR/CD3 proteins from αβ‐ or γδ‐T‐lymphoma‐cell lines, as well as TCRγδ cDNA transfectants, it was found that CD3δ chains associate less strongly with TCRγδ heterodimers compared to TCRαβ heterodimers. This preferential reactivity of CD3δ chains appears to be structural and not owing to differences in γδ‐ versus αβ‐T‐cell intracellular environments. Our results are in accordance firstly, with data from CD3δ‐deficient mice, which have γδ‐T cells but no αβ‐T cells, secondly with the suggested role of CD3δ chains in the positive selection of αβ‐T cells, a process apparently not followed by γδ‐T cells, and lastly with the differential roles of CD3δ chains versus CD3γ chains, explaining the maintenance of two CD3δ and CD3γ genes after the duplication from a CD3δ/γ gene present in avians. The impaired reactivity of CD3δ chains with TCRγδ heterodimers seems to be owing to a less efficient association with TCRγ chains. In contrast, CD3δ chains interact as strongly with TCRδ chains as do CD3γ chains with both TCRγ and TCRδ chains. These data may explain, at the molecular levels, why surface TCR/CD3 expression levels are impaired in γδ‐T cells from CD3γ‐deficient mice but not from CD3δ‐deficient mice.

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“…In mature cells, the ITAMs appear to have overlapping functions and contribute to signaling quantitatively (12)(13)(14). Similarly, in the pre-TCR, substitution of normal CD3, CD3⑀, and CD3␥ subunits with versions in which the ITAM sequences are deleted or mutated can still assemble and fully promote CD4 ϩ 8 ϩ (double positive (DP)) differentiation and expansion (13,(15)(16)(17). It appears that the requirement for different subunits may be more dependent on their relative abilities to promote pre-TCR assembly than on any specific signaling function (18).…”

Section: Tcr␤ Transmembrane Tyrosines Are Required For Pre-tcr Functimentioning

confidence: 99%

TCRβ Transmembrane Tyrosines Are Required for Pre-TCR Function

Spain

Liu

2002

The Journal of Immunology

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The pre-TCR promotes thymocyte development in the αβ lineage. Productive rearrangement of the TCRβ locus triggers the assembly of the pre-TCR, which includes the pTα chain and CD3 εγδζ subunits. This complex receptor signals the up-regulation of CD4 and CD8 expression, thymocyte proliferation/survival, and the cessation of TCRβ rearrangements (allelic exclusion). In this study, we investigate the function of two conserved tyrosine residues located in the TCRβ chain transmembrane region of the pre-TCR. We show that replacement of both tyrosines with alanine and expression of the mutant receptor in RAG-1null thymocytes prevents surface expression and abolishes pre-TCR function relative to wild-type receptor. Replacement of both tyrosines with phenylalanines (YF double mutant) generates a complex phenotype in which thymocyte survival and proliferation are severely disrupted, differentiation is moderately disrupted, and allelic exclusion is unaffected. We further show that the YF double mutant receptor is expressed on the cell surface and associates with pTα and CD3ε at the same level as does wild-type TCRβ, while association of the YF double mutant with CD3ζ is slightly reduced relative to wild type. These data demonstrate that pre-TCR signaling pathways leading to proliferation and survival, differentiation, and allelic exclusion are differently sensitive to subtle mutation-induced alterations in pre-TCR structure.

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A Redundant Role of the CD3γ-Immunoreceptor Tyrosine-Based Activation Motif in Mature T Cell Function

Cited by 34 publications

References 71 publications

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

Human TCR That Incorporate CD3ζ Induce Highly Preferred Pairing between TCRα and β Chains following Gene Transfer

On the Role of CD3δ Chains in TCRγδ/CD3 Complexes during Assembly and Membrane Expression

TCRβ Transmembrane Tyrosines Are Required for Pre-TCR Function

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