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1.
Gammadelta T cell receptors (TCRs), alphabeta TCRs, and antibodies are the three lineages of somatically recombined antigen receptors. The structural basis for ligand recognition is well defined for alphabeta TCR and antibodies but is lacking for gammadelta TCRs. We present the 3.4 A structure of the murine gammadelta TCR G8 bound to its major histocompatibility complex (MHC) class Ib ligand, T22. G8 predominantly uses germline-encoded residues of its delta chain complementarity-determining region 3 (CDR3) loop to bind T22 in an orientation substantially different from that seen in alphabeta TCR/peptide-MHC. That junctionally encoded G8 residues play an ancillary role in binding suggests a fusion of innate and adaptive recognition strategies. 相似文献
2.
Crowley MP Fahrer AM Baumgarth N Hampl J Gutgemann I Teyton L Chien Y 《Science (New York, N.Y.)》2000,287(5451):314-316
Although gammadelta T cells are implicated in regulating immune responses, gammadelta T cell-ligand pairs that could mediate such regulatory functions have not been identified. Here, the expression of the major histocompatibility complex (MHC) class Ib T22 and the closely related T10 molecules is shown to be activation-induced, and they confer specificity to about 0.4% of the gammadelta T cells in normal mice. Thus, the increased expression of T22 and/or T10 might trigger immunoregulatory gammadelta T cells during immune responses. Furthermore, the fast on-rates and slow off-rates that characterize this receptor/ligand interaction would compensate for the low ligand stability and suggest a high threshold for gammadelta T cell activation. 相似文献
3.
Reinherz EL Tan K Tang L Kern P Liu J Xiong Y Hussey RE Smolyar A Hare B Zhang R Joachimiak A Chang HC Wagner G Wang J 《Science (New York, N.Y.)》1999,286(5446):1913-1921
The crystal structure of a complex involving the D10 T cell receptor (TCR), 16-residue foreign peptide antigen, and the I-Ak self major histocompatibility complex (MHC) class II molecule is reported at 3.2 angstrom resolution. The D10 TCR is oriented in an orthogonal mode relative to its peptide-MHC (pMHC) ligand, necessitated by the amino-terminal extension of peptide residues projecting from the MHC class II antigen-binding groove as part of a mini beta sheet. Consequently, the disposition of D10 complementarity-determining region loops is altered relative to that of most pMHCI-specific TCRs; the latter TCRs assume a diagonal orientation, although with substantial variability. Peptide recognition, which involves P-1 to P8 residues, is dominated by the Valpha domain, which also binds to the class II MHC beta1 helix. That docking is limited to one segment of MHC-bound peptide offers an explanation for epitope recognition and altered peptide ligand effects, suggests a structural basis for alloreactivity, and illustrates how bacterial superantigens can span the TCR-pMHCII surface. 相似文献
4.
Shin S El-Diwany R Schaffert S Adams EJ Garcia KC Pereira P Chien YH 《Science (New York, N.Y.)》2005,308(5719):252-255
The molecular basis of gammadelta T cell receptor (TCR) recognition is poorly understood. Here, we analyze the TCR sequences of a natural gammadelta T cell population specific for the major histocompatibility complex class Ib molecule T22. We find that T22 recognition correlates strongly with a somatically recombined TCRdelta complementarity-determining region 3 (CDR3) motif derived from germ line-encoded residues. Sequence diversity around these residues modulates TCR ligand-binding affinities, whereas V gene usage correlates mainly with tissue origin. These results show how an antigen-specific gammadelta TCR repertoire can be generated at a high frequency and suggest that gammadelta T cells recognize a limited number of antigens. 相似文献
5.
Whereas T helper cells recognize peptide-major histocompatibility complex (MHC) class II complexes through their T cell receptors (TCRs), CD4 binds to an antigen-independent region of the MHC. Using green fluorescent protein-tagged chimeras and three-dimensional video microscopy, we show that CD4 and TCR-associated CD3zeta cluster in the interface coincident with increases in intracellular calcium. Signaling-, costimulation-, and cytoskeleton-dependent processes then stabilize CD3zeta in a single cluster at the center of the interface, while CD4 moves to the periphery. Thus, the CD4 coreceptor may serve primarily to "boost" recognition of ligand by the TCR and may not be required once activation has been initiated. 相似文献
6.
Structural mutations of the T cell receptor zeta chain and its role in T cell activation 总被引：23，自引：0，他引：23
S J Frank B B Niklinska D G Orloff M Mer?ep J D Ashwell R D Klausner 《Science (New York, N.Y.)》1990,249(4965):174-177
T cell hybridomas that express zeta zeta, but not zeta eta, dimers in their T cell receptors (TCRs) produce interleukin-2 (IL-2) and undergo an inhibition of spontaneous growth when activated by antigen, antibodies to the receptor, or antibodies to Thy-1. Hybridomas without zeta and eta were reconstituted with mutated zeta chains. Cytoplasmic truncations of up to 40% of the zeta molecule reconstituted normal surface assembly of TCRs, but antigen-induced IL-2 secretion and growth inhibition were lost. In contrast, cross-linking antibodies to the TCR activated these cells. A point mutation conferred the same signaling phenotype as did the truncations and caused defective antigen-induced tyrosine kinase activation. Thus zeta allows the binding of antigen/major histocompatibility complex (MHC) to alpha beta to effect TCR signaling. 相似文献
7.
Self-nonself discrimination by T cells 总被引：28，自引：0，他引：28
The alpha beta T cell receptor (TCR) recognizes antigens that are presented by major histocompatibility complex (MHC)-encoded cell surface molecules by binding to both the antigen and the MHC molecules. Discrimination of self from nonself antigens and MHC molecules is achieved by negative and positive selection of T cells in the thymus: potentially harmful T cells with receptors that bind to self antigens plus self MHC molecules are deleted before they can mount immune responses. In contrast, the maturation of useful T cells with receptors that bind foreign antigens plus self MHC molecules requires the binding of their receptor to MHC molecules on thymic epithelium in the absence of foreign antigen. The binding of the TCR to either class I or class II MHC molecules directs differentiation of the selected cells into either CD4-8+ (killer) or CD4+8- (helper) T cells, respectively. 相似文献
8.
Limit of T cell tolerance to self proteins by peptide presentation 总被引：11，自引：0，他引：11
Cytotoxic T lymphocytes (CTLs) recognize foreign peptides bound to major histocompatibility complex (MHC) class I molecules. MHC molecules can also bind endogenous self peptides, to which T cells are tolerant. Normal mice contained CTLs specific for self peptides that were from proteins of ubiquitous or tissue-restricted expression. In vivo, these endogenous self peptides are not naturally presented in sufficient density by somatic cells expressing MHC class I molecules. They can, however, be presented if added exogenously. Thus, our data imply that CTLs are only tolerant of those endogenous self peptide sequences that are presented by MHC class I-positive cells in a physiological manner. 相似文献
9.
Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice 总被引：32，自引：0，他引：32
M J Grusby R S Johnson V E Papaioannou L H Glimcher 《Science (New York, N.Y.)》1991,253(5026):1417-1420
The maturation of T cells in the thymus is dependent on the expression of major histocompatibility complex (MHC) molecules. By disruption of the MHC class II Ab beta gene in embryonic stem cells, mice were generated that lack cell surface expression of class II molecules. These MHC class II-deficient mice were depleted of mature CD4+ T cells and were deficient in cell-mediated immune responses. These results provide genetic evidence that class II molecules are required for the maturation and function of mature CD4+ T cells. 相似文献
10.
Girardi M Oppenheim DE Steele CR Lewis JM Glusac E Filler R Hobby P Sutton B Tigelaar RE Hayday AC 《Science (New York, N.Y.)》2001,294(5542):605-609
The localization of gammadelta T cells within epithelia suggests that these cells may contribute to the down-regulation of epithelial malignancies. We report that mice lacking gammadelta cells are highly susceptible to multiple regimens of cutaneous carcinogenesis. After exposure to carcinogens, skin cells expressed Rae-1 and H60, major histocompatibility complex-related molecules structurally resembling human MICA. Each of these is a ligand for NKG2d, a receptor expressed by cytolytic T cells and natural killer (NK) cells. In vitro, skin-associated NKG2d+ gammadelta cells killed skin carcinoma cells by a mechanism that was sensitive to blocking NKG2d engagement. Thus, local T cells may use evolutionarily conserved proteins to negatively regulate malignancy. 相似文献
11.
12.
Brefeldin A specifically inhibits presentation of protein antigens to cytotoxic T lymphocytes 总被引：23，自引：0，他引：23
Cytotoxic T lymphocytes (CTLs) recognize foreign antigens, including viral proteins, in association with major histocompatibility complex (MHC) class I molecules. Brefeldin A, a specific inhibitor of exocytosis, completely and reversibly inhibited the presentation of viral proteins, but not exogenous peptides, to MHC class I-restricted CTLs directed against influenza virus antigens. The effect of brefeldin A on antigen presentation correlated with its inhibition of intracellular transport of newly synthesized class I molecules. Brefeldin A is thus a specific inhibitor of antigen processing for class I-restricted T cell recognition. Its effect on antigen presentation supports the idea that exogenous peptide antigens associate with cell surface class I molecules, whereas protein antigens processed via the cytosolic route associate with nascent class I molecules before they leave the trans-Golgi complex. 相似文献
13.
Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells 总被引：22，自引：0，他引：22
T cells that express the T cell receptor V beta 5.2 domain react with the class II major histocompatibility complex (MHC) molecule I-E, and V beta 5.2+ T cells are deleted in mouse strains that express I-E glycoproteins. By examination of genetically defined recombinant inbred (RI) mouse strains, it was found that the deletion was dependent on the expression of I-E and one of a limited number of non-MHC gene products (cotolerogens). The gene encoding one of these cotolerogens maps to chromosome 12 and is linked to the endogenous provirus Mtv-9. These observations suggest that the I-E-mediated and minor lymphocyte-stimulating antigen (Mls)-mediated deletions of alpha beta T cells from the repertoire are similar; both require the expression of a class II MHC glycoprotein and a second non-MHC gene product. 相似文献
14.
Influence of the major histocompatibility complex on positive thymic selection of V beta 17a+ T cells 总被引：10，自引：0，他引：10
A monoclonal antibody was used to show directly positive thymic selection of the T cell repertoire in mouse strains expressing the 17a beta-chain variable domain (V beta 17a) of the T cell receptor. In the absence of the potent tolerizing class II major histocompatibility complex (MHC) molecule, I-E, peripheral expression of V beta 17a+ T cell receptors varied with the MHC haplotype of the mouse strain. In the most extreme case, H-2q mice expressed high peripheral levels of CD4+ V beta 17a+ T cells (14 to 19 percent), whereas H-2b mice expressed low levels (3 to 4 percent). Analysis of (b x q)F1 mice and chimeric mice showed that these differences were determined by positive thymic selection and implicated the thymic epithelium as the controlling cell type. 相似文献
15.
Murata S Sasaki K Kishimoto T Niwa S Hayashi H Takahama Y Tanaka K 《Science (New York, N.Y.)》2007,316(5829):1349-1353
Proteasomes are responsible for generating peptides presented by the class I major histocompatibility complex (MHC) molecules of the immune system. Here, we report the identification of a previously unrecognized catalytic subunit called beta5t. beta5t is expressed exclusively in cortical thymic epithelial cells, which are responsible for the positive selection of developing thymocytes. Although the chymotrypsin-like activity of proteasomes is considered to be important for the production of peptides with high affinities for MHC class I clefts, incorporation of beta5t into proteasomes in place of beta5 or beta5i selectively reduces this activity. We also found that beta5t-deficient mice displayed defective development of CD8(+) T cells in the thymus. Our results suggest a key role for beta5t in generating the MHC class I-restricted CD8(+) T cell repertoire during thymic selection. 相似文献
16.
Shen Y Zhou D Qiu L Lai X Simon M Shen L Kou Z Wang Q Jiang L Estep J Hunt R Clagett M Sehgal PK Li Y Zeng X Morita CT Brenner MB Letvin NL Chen ZW 《Science (New York, N.Y.)》2002,295(5563):2255-2258
To examine the role of T cell receptor (TCR) in gammadelta T cells in adaptive immunity, a macaque model was used to follow Vgamma2Vdelta2+ T cell responses to mycobacterial infections. These phosphoantigen-specific gammadelta T cells displayed major expansion during Mycobacterium bovis Bacille Calmette-Guérin (BCG) infection and a clear memory-type response after BCG reinfection. Primary and recall expansions of Vgamma2Vdelta2+ T cells were also seen during Mycobacterium tuberculosis infection of naive and BCG-vaccinated macaques, respectively. This capacity to rapidly expand coincided with a clearance of BCG bacteremia and immunity to fatal tuberculosis in BCG-vaccinated macaques. Thus, Vgamma2Vdelta2+ T cells may contribute to adaptive immunity to mycobacterial infections. 相似文献
17.
18.
Structure and specificity of a class II MHC alloreactive gamma delta T cell receptor heterodimer 总被引：7，自引：0，他引：7
L A Matis A M Fry R Q Cron M M Cotterman R F Dick J A Bluestone 《Science (New York, N.Y.)》1989,245(4919):746-749
Two distinct CD3-associated T cell receptors (TCR alpha beta and TCR gamma delta) are expressed in a mutually exclusive fashion on separate subsets of T lymphocytes. While the specificity of the TCR alpha beta repertoire for major histocompatibility complex (MHC) antigens is well established, the diversity of expressed gamma delta receptors and the ligands they recognize are less well understood. An alloreactive CD3+CD4-CD8- T cell line specific for murine class II MHC (Ia) antigens encoded in the I-E subregion of the H-2 gene complex was identified, and the primary structure of its gamma delta receptor heterodimer was characterized. In contrast to a TCR alpha beta-expressing alloreactive T cell line selected for similar specificity, the TCR gamma delta line displayed broad cross-reactivity for multiple distinct I-E-encoded allogeneic Ia molecules. 相似文献
19.
Murali-Krishna K Lau LL Sambhara S Lemonnier F Altman J Ahmed R 《Science (New York, N.Y.)》1999,286(5443):1377-1381
An understanding of how T cell memory is maintained is crucial for the rational design of vaccines. Memory T cells were shown to persist indefinitely in major histocompatibility complex (MHC) class I-deficient mice and retained the ability to make rapid cytokine responses upon reencounter with antigen. In addition, memory CD8 T cells, unlike na?ve cells, divided without MHC-T cell receptor interactions. This "homeostatic" proliferation is likely to be important in maintaining memory T cell numbers in the periphery. Thus, after na?ve CD8 T cells differentiate into memory cells, they evolve an MHC class I-independent "life-style" and do not require further stimulation with specific or cross-reactive antigen for their maintenance. 相似文献
20.
F B Wells S J Gahm S M Hedrick J A Bluestone A Dent L A Matis 《Science (New York, N.Y.)》1991,253(5022):903-905
The alpha beta and gamma delta T cell receptors for antigen (TCR) delineate distinct T cell populations. TCR alpha beta-bearing thymocytes must be positively selected by binding of the TCR to major histocompatibility complex (MHC) molecules on thymic epithelium. To examine the requirement for positive selection of TCR gamma delta T cells, mice bearing a class I MHC-specific gamma delta transgene (Tg) were crossed to mice with disrupted beta 2 microglobulin (beta 2M) genes. The Tg+beta 2M- (class I MHC-) offspring had Tg+ thymocytes that did not proliferate to antigen or Tg-specific monoclonal antibody and few peripheral Tg+ cells. This is evidence for positive selection within the gamma delta T cell subset. 相似文献