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1.
Eric J. Jenkinson Graham Anderson Nel C. Moore Christopher A. Smith John J. T. Owen 《Clinical & developmental immunology》1994,3(4):265-271
We have investigated the possibility that the costimulatory signals required for activation of
mature T cells also play a role in providing differentiation signals for positive selection
during T-cell development. We show that purified MHC Class II+ thymic epithelial cells are
able to support positive selection in vitro but lack both the functional capacity to deliver
costimulatory signals and expression of the costimulatory ligand B7. Our results suggest that
the additional signals provided by costimulatory ligands are not required for TCR-mediated
positive selection, although other ancillary signals provided by thymic epithelial cells may
be involved. 相似文献
2.
Yujiro Tanaka Clio Mamalaki Brigitta Stockinger Dimitris Kioussis 《European journal of immunology》1993,23(10):2614-2621
We have established conditionally immortalized thymic cortical epithelial cell lines from transgenic mice carrying a temperature-sensitive SV40 large Tantigen. One of these cell lines expresses cortical markers and produces IL-1α, IL-6, IL-7, and TGF-β1. These cells express class I major histocompatibility complex (MHC) constitutively and class II MHC upon induction with IFN-μ. The cells appear to have a normal class I antigen presenting pathway since messages for both peptide transporter genes (TAP1, TAP2) were detected. The ability of these cortical epithelial cells to present peptide antigen was compared to that of thymic dendritic cells. In suspension culture with αβ Tcell receptor (TcR) transgenic thymocytes, these epithelial cells and dendritic cells (pre-pulsed with peptide cognate for the transgenic TcR) caused down-regulation of CD4, CD8, and TcR in an antigen dose-dependent and MHC-restricted manner. CD4dullCD8dull cells were taken as evidence for negative selection because these cells contained apoptotic DNA. Concentration of peptide required for negative selection of thymocytes was similar between dendritic cells and cortical epithelial cells. In contrast, αβ transgenic spleen cells were activated only by dendritic cells but not by cortical epithelial cells. 相似文献
3.
Paul Waterhouse Martin F. Bachmann Josef M. Penninger Pamela S. Ohashi Tak W. Mak 《European journal of immunology》1997,27(8):1887-1892
CTLA-4 is a T cell surface receptor essential for the negative regulation of T cell activation. In the CTLA-4-deficient mouse, a dramatic accumulation of activated peripheral T cells effects extensive damage to host tissues, resulting in mortality within 5 weeks of age. To determine whether the accumulation of activated T cells in CTLA-4?/? mice is due to a defect in thymic selection, we examined negative selection in CTLA-4?/? mice using two transgenic T cell receptor (TCR) models of thymic selection. Neither the H-Y-specific TCR nor the lymphocytic choriomeningitis virus (LCMV)-specific TCR transgenic models revealed a defect in positive or negative selection in CTLA-4?/? mice in vivo or in vitro. In fact, the negatively selecting phenotype of male H-YTCR-transgenic mice greatly mitigated the accumulation of activated peripheral T cells. Further, peripheral CTLA-4?/? T cells expressing a single LMCV-specific transgenic TCR did not have an activated phenotype, indicating that CTLA-4?/? T cells require specific antigen for proliferation. These results demonstrate that specific antigen is required for the lymphoproliferation observed in CTLA-4?/? mice, and that CTLA-4 deficiency does not lead to a gross defect in negative selection. 相似文献
4.
5.
Owen Williams Yujiro Tanaka Mark Bix Marianna Murdjeva Dan R. Littman Dimitris Kioussis 《European journal of immunology》1996,26(3):532-538
The T cell receptor (TCR) recognizes antigenic peptide presented by major histocompatibility complex (MHC) molecules. Analogs of antigenic peptides have been shown to inhibit antigen-specific T cell responses, a phenomenon described as TCR antagonism. We have examined the effect of a natural variant of an antigenic peptide and a synthetic peptide analog, on the responses of mature T cells and immature thymocytes from an αβ TCR-transgenic mouse (F5), the TCR of which recognizes a nonamer peptide from the nucleoprotein (NP) of influenza virus in the context of the H-2Db MHC molecule. Both peptides were shown to antagonize specifically the T cell cytolytic response without being able directly to stimulate mature T cells from these transgenic mice. Furthermore, a negative selection assay in vitro was used to demonstrate for the first time that antagonistic peptides are capable of antagonizing thymocyte deletion induced by antigenic peptides. These data suggest that the final selection of a T cell could be the result of a balance between the positive and negative influences of endogenous peptide ligands. 相似文献
6.
Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes 总被引:2,自引:0,他引:2
Unlike meduilary thymic epithelial cells (TEC) of normal mice,meduilary TEC of TCR– SCID mice are immature and disorganized.In order to assess directly the role of TCR+ cells in the developmentof medullary TEC, we bred mice which co-expressed the SCID geneticdefect and transgenes encoding clonotypic TCR chains. Immunohistologicexamination revealed that meduilary thymic epithelial cellsfrom TCRß transgenic SCID mice, whose thymocytes onlyexpress TCRß chains that inefficiently associate withCD3 and , components, remained immature and disorganized. Incontrast, meduilary TEC from TCRß transgenic SCIDmice, whose thymocytes express fully assembled CD3--TCRßcomplexes were mature and organized. Interestingly, the abilityof TCRß+-+-CD33 thymocytes to induce maturation ofmeduilary TEC appeared not to be related to the antigen specificityof the TCR as thyml from positively selecting, negatively selectingand non-selecting TCRß transgenic SCID mice all possessedinduced meduilary thymic epithelial cells. In addition, we foundthat induction of meduilary TEC cells was associated with thepresence of meduilary thymocytes, including those of the CD4-CD8-TCRß+phenotype. The present findings demonstrate that fully assembledCD3--TCR complexes are required to induce maturation of meduilarythymic epithelial cells and indicate that thymocyte inductionof meduilary thymic epithelial cells may result from signalingindependently of their clonotyplc chains. 相似文献
7.
Quantitative theories of T-cell responsiveness 总被引:1,自引:0,他引:1
Summary: We review recent advances toward a comprehensive mathematical theory of T-cell immunity. A key insight is that the efficacy of the T-cell response is best analyzed in terms of T-cell receptor (TCR) avidity and the distribution of this avidity across the TCR repertoire (the 'avidity spectrum'). Modification of this avidity spectrum by a wide range of tuning and tolerance mechanisms allows the system to adapt cross-reactivity and specificity to the challenge at hand while avoiding inappropriate responses against non-pathogenic cells and tissues. Theoretical models relate molecular kinetic parameters and cellular properties to systemic level statistics such as avidity spectra. Such bridge equations are crucial for rational clinical manipulation of T cells at the molecular level. 相似文献
8.
Tong Zhou Martin Fleck Ulf Müeller-Ladner Pingar Yang Zheng Wang Steffen Gay Shigeru Matsumoto John D. Mountz 《Journal of clinical immunology》1997,17(1):74-84
Although most thymocytes express high levels of Fas antigen (CD95), the role of Fas in apoptosis signaling during thymocyte maturation has not been defined. Fas apoptosis occurs primarily in the CD4+CD8+ subpopulations of thymocytes. Fas expression and apoptosis function were investigated in the CD4–8–, CD4+8+, and CD4+ and CD8 single positive thymocyte subpopulations by in vivo injection of anti-Fas and in vitro incubation of Fas with thymic organ cultures. Fas was first expressed on CD4–8– thymocytes coincident with expression of IL-2R and CD44. In Fas mutant lpr/lpr mice, defective Fas expression correlated with overproduction of late-stage CD4–8–-thymocytes. Fas was highly expressed on CD3dull and CD3bright thymocytes. CD4+8+CD3dull thymocytes were sensitive to Fas apoptosis, whereas more mature CD4+8+CD3bright thymocytes were resistant to Fas apoptosis. Anti-Fas incubation with established thymic organ culture for 24 hr resulted in apoptosis of approximately 25% of thymocytes. Continued incubation of thymic organ culture with anti-Fas resulted in an apoptosis rate of 25% of CD4+CD8+ thymocytes per day for the first 3 days of culture. Continued culture for further time points up to 6 days did not result in further apoptosis of the CD4+CD8+ thymocytes. These results suggest that CD4–CD8–CD44+ IL-2R+ thymocytes express Fas and there is overpopulation of the subsequent developmental stage of thymocytes in Fas mutant lpr mice. Also, early-stage CD4+8+ thymocytes are susceptible to Fas apoptosis, whereas Fas apoptosis resistance is required after 3 days of thymic organ culture. We conclude that these two populations of thymocytes are susceptible to Fas ligand-mediated apoptosis during T cell development in the thymus. 相似文献
9.
The Standard model of T cell recognition asserts that T cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus and that peripheral T cell repertoire has mild self‐major histocompatibility complex (MHC) reactivity, known as MHC restriction of foreign antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope models suggest contradictory roles for complementarity‐determining regions (CDRs) of the TCRs. Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR‐MHC–conserved interaction. I suggest that double (CD4+CD8+)‐positive (DP) developing thymocytes compete with their αβTCRs for binding to self‐pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue‐restricted antigens. The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal‐centre B cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self‐pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4+ Foxp3+ tTregs can be generated by mTECs via Aire‐dependent and Aire‐independent pathways, and additionally on thymic bone marrow–derived APCs including thymic Aire‐expressing B cells. Thymic Tregs differ from the induced peripheral Tregs, which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes’ competition for the highest binding to self‐pMHC is the co‐evolution of species‐specific αβTCR V regions with MHC alleles. 相似文献
10.
11.
M Coli? N Pejnovi? M Kataranovski N Stojanovi? T Terzi? A Duji? 《International immunology》1991,3(11):1165-1174
To study the in vitro interactions between rat thymic non-lymphoid cells and thymocytes, we established a system for long-term cultivation of thymic epithelial cells (TEC). TEC were cultivated and successfully propagated for over 8 months in RPMI 1640 medium containing 15% FCS, dexamethasone, insulin, epidermal growth factor, and poly-L-lysin as an adhesive matrix. Their epithelial nature has been confirmed using monoclonal anti-cytokeratin (CK) antibodies. More than 95% of these cells were reactive with K 8.13 and CK 8 mAbs, which are pan-epithelial markers for rat TEC in situ. An epithelial cell clone (TE-R 2.5) established from a long-term TEC culture was 100% reactive with these anti-CK antibodies. Phenotypic analysis of TEC cultures was performed by a large panel of mAbs reactive with a subset of rat TEC or CK polypeptides as well as UIex europaeus agglutinin I using a streptavidin-biotin immunofluorescence assay. Although the results obtained demonstrated phenotypic heterogeneity among these cells, most cultures, including the TE-R 2.5 clone, were of subcapsular/medullary phenotype. Medium conditioned by TEC cultures exhibited IL-1 and IL-6 activities when tested on D10S and B9 sensitive cell lines, respectively. Cytokine activities were neutralized (IL-1) or significantly inhibited (IL-6) by specific polyclonal antibodies. In addition, both anti-IL-1 and anti-IL-6 antibodies reacted with TEC in culture and epithelial (CK-positive) cells on thymic cryostat sections, indicating that thymic epithelium provides an important intrathymic source for molecules contributing to T cell activation. 相似文献
12.
13.
Crystallographic studies suggest a plausible divalent interaction between T-cell receptor (TCR) and MHC class II molecules. In addition, biochemical data suggest that these divalent MHC molecules are preformed at the membrane of the antigen-presenting cell. The tetramer model is based on these preformed tetrameric class II molecules that can be loaded with identical or different peptides in their two grooves. This enables divalent class II molecules to deliver two different messages to T cell: 1) a two-peptide message, in which the tetramer with two identical peptides is able to cross-link two TCRs triggering full activation of a T cell. At the thymic level we propose that this message induces negative selection; or 2) a one-peptide message: only one of the peptides loaded in the class II tetramer is able to interact with that TCR. This message would be involved in triggering partial activation phenomena in mature lymphocytes, whereas in thymocytes this message would mediate positive selection. Since high concentrations of a peptide would favor the load of tetramers with identical peptides, the tetramer could therefore be viewed as a quantitative-qualitative transducer that would trigger different responses depending on the concentration of antigenic peptides. 相似文献
14.
The chicken thymic microenvironment, as it developed in an embryonic thymus organ
culture system, was phenotypically mapped using a panel of mAb defining both
epithelial and nonepithelial stromal cell antigens. We have previously reported that
thymocyte proliferation and differentiation will proceed for up to 6–8 days in thymus
organ culture, hence demonstrating the functional integrity of the thymic
microenvironment in vitro. During this time, the stromal component reflected that of the
normal embryo with cortical and medullary epithelial areas readily identifiable by both
morphology and surface-antigen expression. An abundance of subcapsular and cortical
epithelial antigens was detected in the cultured thymus, particularly those normally
expressed by the epithelium lining the capsule, trabeculae, and vascular regions (type
epithelium) in the adult and embryonic thymus. Medullary epithelial antigens
developed in organ culture, although were present in lower frequency than observed in
the age-matched embryonic thymus. MHC class II expression by both epithelial and
nonepithelial cells was maintained at high levels throughout the culture period. With
increasing time in culture, the ratio of epithelial to nonepithelial cells decreased,
concurrent with a decrease in thymocyte frequency and suggestive of a bidirectional
interaction between these two cell types. Thus, a functionally intact thymic
microenvironment appears to be maintained in embryonic thymus organ culture, a
model that is currently being exploited to assess the role of stromal antigens, as defined
by our mAb, in the process of thymopoiesis. 相似文献
15.
R.N.P. Cahill W.G. Kimpton C.P. Cunningham E.A. Washington 《Seminars in immunology》1997,9(6):355-363
Lymphocyte recirculation is an essential element in the integration of immune responses and is an absolute requirement for the development of systemic memory in postnatal animals. During foetal life a large pool of recirculating T cells develops and migration pathways of naive T cells to skin and peripheral tissues as well as LN are established. At birth a process is triggered whereby naive fetal T cells are rapidly lost from the circulating pool and are replaced by newly arriving T cells which have been formed since birth. At present our data suggest that the thymic export in the fetus creates a pool of long-lived naive T cells of wide diversity. The situation in neonatal lambs is more complex since the thymus is exporting large numbers of short-lived thymic emigrants which enter a peripheral T-cell population where many T cells are dividing. 相似文献
16.
17.
A culture system for the study of pancreatic organogenesis 总被引:3,自引:0,他引:3
Summary Methods of microdissection and culture are described for the establishment and short-term maintenance of cultures derived
from early embryonic mouse pancreas. Varying culture conditions may be employed to study aspects of epithelio-mesenchymal
interactions in the developing pancreas. 相似文献
18.
Analysis of antigen-induced negative selection of thymocytes in T cell receptor (TCR)-transgenic mice is complicated by the presence of an antigen-responsive peripheral T cell compartment. Our experiments address the question of whether and how peripheral T cell activation can affect immature thymocytes. Following three daily injections of peptide antigen into mice expressing a peptide-specific transgenic TCR and deficient for TAP1, we and others have found profound deletion of the CD4+CD8+ (DP) thymocyte subset. However, our work shows that even though mature CD8+ T cells are inefficiently selected in TAP1-deficient mice, there was a striking degree of peripheral expansion and activation of CD8+ peripheral T cells. Furthermore, when cells from TCR-transgenic mice were adoptively transferred, we found that deletion of non-transgenic DP thymocytes occurred in Thy-1-congenic and even more efficiently in TAP1-deficient recipients after repeated peptide injection resulting in peripheral T cell activation. In the adoptive transfer experiments the degree of deletion of immature bystander thymocytes was decreased upon blocking of TNF. These data show that deletion of DP thymocytes can result from excessive peripheral T cell activation and identify TNF as an important effector molecule for this process. When steps are taken to avoid peripheral T cell activation, peptide antigen can induce TCR-mediated thymocyte deletion, presumably in the thymus cortex, since injection of TAP1-deficient TCR-transgenic mice resulted in deletion of immature DP thymocytes prior to detectable peripheral T cell expansion and activation. This effect was not blocked by inhibiting tumor necrosis factor activity. In addition, DP depletion was seen in the absence of peripheral T cell activation when antibody-mediated depletion of CD8+ T cells was performed. Our work clearly shows that two mechanisms for deletion of DP thymocytes exist: deletion induced by antigen presentation in the thymus and deletion as a consequence of repeated stimulation of mature peripheral T cells. 相似文献
19.
Lannes-Vieira Joseli; Chammas Roger; Villa-Verde Dea M. S.; Vannier-dos-Santos Marcos A.; Mello-Coelho Valeria; de Souza Sandro Jose; Brentani Ricardo Renzo; Savino Wilson 《International immunology》1993,5(11):1421-1430
We describe herein the expression of the VLA6 complex by murinethymic epithelial cells (TEC). The immunohistochemical distributionrevealed that VLA6 is found in both thymic medullary and subcapsullaryareas. Moreover, studies by immunoelectron microscopy revealeda membrane labeling of the VLA6 molecule, including at desmosomalsites. By means of immunoblottlng, immunoprecipitation, andaffinity chromatography of extracts from a mouse TEC line, wefurther demonstrated that VLA6 is a laminin (LN) receptor inthese cells. In keeping with this finding, we showed that TECadhesion, spreading, and proliferation were enhanced in vitroby LN. The fact that VLA6 is also expressed by the large majorityof thymocytes raised the hypothesis that it might be involvedin LN-mediated TEC—thymocyte interactions. Interestingly,in vitro experiments showed that there is an increase in theTEC—thymocyte adhesion upon glucocorticold hormone treatment,a situation in which the expression of VLA6 as well as LN isenhanced. Most importantly, this adhesion can be reversed bypre-treating TEC with an anti-6 integrin mAb. Additionally,spontaneous in vitro thymocyte release by thymic nurse cellcomplexes was enhanced by LN and partially blocked by anti-6or anti-ß1 antibodies. Our results suggest that VLA6is involved in LN-mediated TEC—thymocyte interactionsthat can be relevant for thymic microenvironmental cell physiologyand intrathymic T cell differentiation events. 相似文献
20.
Lucia Renata Meireles de Souza Valeria Trajano Wilson Savino 《Clinical & developmental immunology》1993,3(2):123-135
Thymic epithelial cells (TEC) heterogeneity suggests the existence of functional subsets.
Anti-cytokeratin (Anti-CK) monoclonal antibodies (MAb), markers of epithelial
differentiation, have been used to detect TEC subsets in rodents and humans. These
MAb revealed a different topography of CK-defined TEC subsets in mice and humans,
leading us to carry out a comparative study of mammalian thymuses. Our study
showed that the distribution pattern of cytokeratins in the thymic epithelium is complex
and unique, with coexpression of CK typical of simple and stratified epithelia.
Moreover, we demonstrated an interspecific diversity of CK expression within the
thymic lobules. Interestingly, such diversity was not a general phenomenon for the
expression of any thymic microenvironmental proteins, because the location of
extracellular matrix components was essentially similar in the mammalian species
studied. 相似文献