Molecular and genetic insights into T cell antigen receptor signal transduction.
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Amino Acid Sequence↗
Biomedical subjects
M Iwashima
Publications and source records attributed to M Iwashima.
ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain.
Protein-tyrosine kinases (PTKs) play an integral role in T cell activation. Stimulation of the T cell antigen receptor (TCR) results in tyrosine phosphorylation of a number of cellular substrates. One of these is the TCR zeta chain, which can mediate the transduction of extracellular stimuli into cellular effector functions. We have recently identified a 70 kd tyrosine phosphoprotein (ZAP-70) that associates with zeta and undergoes tyrosine phosphorylation following TCR stimulation. Here we report the isolation of a cDNA clone encoding ZAP-70. ZAP-70 represents a novel PTK and is expressed in T and natural killer cells. Moreover, tyrosine phosphorylation and association of ZAP-70 with zeta require the presence of src family PTKs and provide a potential mechanism by which the src family PTKs and ZAP-70 may interact to mediate TCR signal transduction.
Amino Acid Sequence↗
Regulation of protein tyrosine kinase activation by the T-cell antigen receptor zeta chain.
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Amino Acid Sequence↗
A gamma/delta cell receptor heterodimer induces the expression of CD4 and CD8 in thymocytes.
CD4 and CD8 have been useful surface markers for alpha/beta T cell maturation. In an alpha/beta T cell receptor (TCR) transgenic SCID mice system, it has been shown that alpha/beta TCR alone is sufficient to induce CD4 and CD8 surface expression on thymic T cells. Although the late embryonic thymic gamma/delta T cells are predominately single and double positive, it has not been clear if gamma/delta TCR has a similar capacity. In this study, we show that when transgenes encoding the earliest embryonic gamma/delta TCR are coexpressed with the SCID defect, the gamma/delta transgenes promote the appearance of both the CD4-8- and CD4+8+ T cells in the thymus. Furthermore, the expression of CD4 and CD8 does not require continuous surface gamma/delta TCR expression. These results indicate that gamma/delta TCR alone can promote the CD4/8 surface expression, and may suggest a role for gamma/delta T cells in initiating normal thymic ontogeny.
Animals↗
Expression of a fetal gamma delta T-cell receptor in adult mice triggers a non-MHC-linked form of selective depletion.
Day 14 fetal thymocytes and adult dendritic epidermal T cells (dEC) of all mouse strains express a characteristic non-polymorphic gamma delta T-cell receptor which is rarely found in the adult thymus or lymph nodes. We have made transgenic mice expressing this particular set of receptors on T cells in C3H and C57BL/6 mice. In adult mice of the latter strain, a dramatic depletion of transgene expressing T cells occurs and this effect is primarily mediated by thymic radiosensitive cells. The depletion is genetically dominant but not MHC-linked with major factor(s) mapping to chromosome 18. Taken together, our results show that strain-specific developmental changes in the thymic environment may play a role in shaping the gamma delta TCR repertoire.
Animals↗
A possible basis for major histocompatibility complex-restricted T-cell recognition.
Four distinct T-cell antigen-receptor gene loci have now been identified and partly characterized: alpha, beta, gamma and delta. All of these loci can rearrange in an immunoglobulin-like fashion and express polypeptides that contribute to either alpha:beta or gamma:delta T-cell receptor-CD3 complexes. Surprisingly, the T-cell receptor (TCR) delta coding regions are located entirely, or almost entirely, within the TCR alpha locus and share at least some of the V region gene segments, thus at least partly linking the two different types of receptor heterodimers. Analysis of potential T-cell receptor diversity, particularly that of the delta chain, indicates a striking concentration of somatic polymorphism in the V-J junctional region of the two heterodimers, four to six orders of magnitude higher than similar calculations for immunoglobulin light- and heavy-chain combinations. In contrast, the number of possible V region combinations in T-cell receptors is one hundredth to one thousandth that of immunoglobulins. TCR alpha: beta heterodimers are known to recognize many possible fragments of antigens embedded in the peptide-binding clefts of a relatively small number of major histocompatibility complex (MHC) molecules. Thus it is attractive to speculate that the V-J junctional portions of both types of T-cell receptor contact peptide antigens, whereas the remaining diversity regions contact the MHC. This contention is supported by molecular modelling studies and has interesting implications for the evolution of antigen-receptor genes.
Antibody Diversity↗
Variable region (V delta) gene segment most frequently utilized in adult thymocytes is 3' of the constant (C delta) region.
A variable region (V delta 5) of the T-cell receptor (TcR) delta chain that is preferentially expressed in adult murine thymocytes is located 2.5 kilobases 3' of the constant region (C delta) element. The V delta 5 coding sequence is in a transcriptional orientation opposite the J delta (joining region) and C delta coding elements and rearranges by inversion. The C delta is divided into four exons, three of which encode amino acids of TcR delta polypeptide, and the fourth comprises the entire 3' untranslated region. In this respect, C delta resembles C alpha rather than C beta or C gamma.
Amino Acid Sequence↗
Alterations in the proliferative response of T cells from aged and chimeric mice.
Factors involved in the nonspecific and specific proliferative responses of T cells were examined in the A/J strain of mice that were physiologically aged in the specific pathogen-free condition. In aged A/J mice, the production of IL-1 and IL-2 from optimally stimulated peritoneal macrophages and splenic T cells was significantly decreased, while the production of IL-3 by T cells was increased. T cells from old mice showed a higher threshold for concanavalin A stimulation for the induction of IL-2 receptors. The same T cells responded only slightly in the mixed lymphocyte reaction (MLR) stimulated by allogeneic class II antigens, while they showed a high background stimulation without stimulators. The addition of syngeneic accessory cells did not increase the proliferative response of T cells from aged animals. T cells from bone marrow chimeras constituted by transferring stem cells from young A/J into irradiated old B10.A mice (young A/J----old B10.A chimeras) showed a pattern very similar to that of old A/J T cells, whereas those from the old A/J----young B10.A chimeras exhibited a response pattern comparable to that of normal young A/J cells. These results indicated that the proliferative responses in aged animals are abnormal, partially due to the alterations in the interleukin cascade. Some changes are probably due to the effect of environment where T cells undergo early differentiation, because bone marrow stem cells from aged mice can generate T cells with normal functions when differentiated in the young environment.
Aging↗
A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation.
A new T-cell receptor gene lies just 5' to the J alpha C alpha coding regions. Its placement in this location suggests a novel mechanism for the regulation of expression of one T-cell receptor polypeptide to another during ontogeny. Rearrangement of this locus occurs very early in thymic differentiation and its RNA expression parallels that of the gamma-chain in thymic subpopulations, making this a possible candidate for the recently described delta-chain of the T-cell receptor.
Animals↗
T-cell receptor delta gene rearrangements in early thymocytes.
The T-cell receptor delta-chain variable region can be assembled from as many as four distinct gene segments, V, D1, D2 and J, more than any other antigen-receptor gene. In fetal thymocytes V----D joinings are as common as D----J or VDJ rearrangements and one V gene segment predominates. Analysis of rearrangements at TCR gamma and delta loci during fetal ontogeny suggests abrupt changes and possible coordinate control in the rearrangement and expression of these loci.
Age Factors↗