A Novel Integrin Involved in Thymocyte-Thymic (original) (raw)
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Role of β2 Integrins in the Binding of Thymocytes to Rat Thymic Macrophages
Clinical & Developmental Immunology, 1994
A role of 32 integrins and one of their ligands, ICAM-1, in thymic macrophage (TMF)/thymocyte interactions was studied. TMF were isolated as adherent cells from 4-day old culture of thymic-cell suspensions either from normal or hydrocortisone-treated rats. Adherent cells were 94-98% positive with ED1 (a pan-macrophage marker). The majority of them (75-95%) expressed the CD11b and CD18 molecules, and 60-70% expressed CD54 (ICAM-1). A low proportion of TMF (10-20%) expressed CDlla (LFA-1). The expression of all these antigens was upregulated by IFN-3 and TNF-a. The effect of these mAbs on TMF/thymocyte binding was studied using a simple rosette assay by incubating unstimulated or IFN-3 or TNF-a stimulated TMF, grown on microscopic slides with resting or ConA +IL-2 activated thymocytes. It was found that LFA-1/CD18 and ICAM-1 play a significant role in the TMF/thymocyte adhesion. In addition, a LFA-l-dependent/ICAM-1-independent adhesion pathway was observed, suggesting that LFA-1 might use another ligand. The inhibitory effect of anti-CD18 mAb (WT-3) was higher than the effect of anti-LFA-1 mAb (WT-1) and was a consequence of blocking the CD18 chain both on thymocytes and TMF. No significant difference in the expression and function of adhesion molecules was found between TMF obtained from normal or hydrocortisone-treated rats. The involvement of CD1 lb in these processes was of lesser importance than the role of the CD11a molecule. By using mAbs to different epitopes of the CD11b molecule, such as OX-42 (anti-CD11b/CD11c), ED7, and ED8 (anti-CD11b), it was found that they were either slightly or moderately inhibitory under certain experimental conditions or did not significantly modulate TMF/thymocyte binding. OX-42 was slightly stimulatory in some experiments. Cumulatively, these results show that 2 integrins play a significant role in TMF/thymocyte interactions and probably contribute to T-cell development in vivo.
Blood, 1998
T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and β (β1 and β4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6β4 lined the basal surface of TEC monolayers, whereas 3β1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3β1 and 6β4 became highly enriched also at the boundaries with adherent thymocytes. ...
Developmental Immunology, 2000
T cell precursors homed to thymus develop in close contact with stromal cells. Among them, thymic epithelial cells (TEC) are known to exert dominant roles in their survival and functional shaping. Key molecules mediating TEC/thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact. Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated, whereas little is known on the opposite phenomenon. We have previously investigated this issue in a co-culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes. We demonstrated that thymocytes adhere to TEC involving [ and [34 integrins and induce the clustering of (z3[ and 6134 heterodimers at the TEC surface. In addition thymocyte adhesion was followed by activation of NF-zB and NF-IL6 gene transciption factors and enhanced IL-6 production. The two latter phenomena were reproduced by the cross-linking of the 3, 6, [31 and [34 integrins, thus implying that the 3131 and z6134 heterodimers can signal during thymocyte adhesion. We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset. We found that adhesion of unstimulated T cell i) involved 1, but not 4 integrin functions at the surface ii) induced the clustering of 3[31, but not c21 heterodimers at the TEC surface and iii) up-regulated the nuclear binding activity of NF-r,B transcription factor and the IL-6 secretion. We propose that 31 and 64 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development.
Blood, 1998
T-cell precursors develop within the thymus in contact with multiple supportive elements, among which thymic epithelial cells (TEC) are known to exert a dominant role in their homing, survival, and functional differentiation. All these functions are supported by cell-cell contacts and cytokine release. Signaling events triggered in lymphoid cells by adhesion to TEC are well characterized, but little is known about the opposite phenomenon. To address this issue, we derived cultures of TEC from human normal thymus. TEC monolayers were cocultured with thymocytes and immunostained with monoclonal antibodies (MoAbs) to integrin (2, 3, 4, and 6) and beta (beta1 and beta4) chains. Optical and confocal analysis showed that integrins were polarized on TEC at discrete surface locations: 6beta4 lined the basal surface of TEC monolayers, whereas 3beta1 was found mostly at TEC-TEC contacts; it is noteworthy that both 3beta1 and 6beta4 became highly enriched also at the boundaries with adherent t...
Developmental immunology, 1998
The seeding and colonization of the thymus by bone marrow stem cells and the maturation of these cells into mature T lymphocytes are dependent on cell-surface recognition events between different cell lineages within the thymic microenvironment. Positive and negative selection processes within the thymus produce a peripheral T-cell repertoire capable of recognizing peptides derived from foreign antigen bound to self MHCmolecules. In addition to the TCR/MHC-peptide interaction, many other cell-surface molecules act in concert to regulate the kinetics of cellular interactions and intracellular signaling events during thymopoiesis. We have investigated the complexity of the thymic stroma by using monoclonal antibodies to clone cell-membrane molecules of thymic stromal cells. Thymic-shared antigen-1 (TSA-1) is a molecule of interest because it is expressed by both immature thymocytes and stromal cells. We report herein the structural and evolutionary relationships between TSA-1 and mole...
Genetic analysis of integrin activation in T lymphocytes
Immunological Reviews, 2002
Summary: Among the myriad receptors expressed by T cells, the sine qua non is the CD3/T cell receptor (CD3/TCR) complex, because it is uniquely capable of translating the presence of a specific antigen into intracellular signals necessary to trigger an immune response against a pathogen or tumor. Much work over the past 2 decades has attempted to define the signaling pathways leading from the CD3/TCR complex that culminate ultimately in the functions necessary for effective T cell immune responses, such as cytokine production. Here, we summarize recent advances in our understanding of the mechanisms by which the CD3/TCR complex controls integrin-mediated T cell adhesion, and discuss new information that suggests that there may be unexpected facets to this pathway that distinguish it from those previously defined.
Expression of functionally active alpha4beta1 integrin by thymic epithelial cells
Clinical and Experimental Immunology, 1996
We have investigated the expression and function of the VLA-4 heterodimer ® 4¯1 , a member of the¯1 integrin subfamily, on human thymic epithelial cells (TEC) derived from cortical epithelium. The expression of the ® 4 integrin chain was studied in four different cloned TEC lines derived from either fetal or post-natal human thymus by both flow cytometry and immunoprecipitation techniques with anti-® 4 MoAbs. All different cell lines assayed expressed significant levels of ® 4 , as revealed by their reactivity with MoAbs specific for distinct ® 4 epitopes. The ® 4 subunit expressed by TEC was associated to¯1 but not to¯7 chain, and displayed the characteristic 80/70 kD pattern of proteolytic cleavage. The VLA-4 integrin in these cells was constitutively active in terms of adhesiveness to both fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In addition, this heterodimer localized to punctate regions of the cell in the area of contact with the substratum, named point contacts assessed by staining with the anti-¯1 activation epitope 15/7 MoAb. According to the cortical origin of the TEC lines expressing VLA-4, human thymus sections stained with different anti-® 4 antibodies revealed the presence of cortical, and in smaller numbers medullary epithelial cells bearing ® 4 integrin. The expression of ® 4 in the thymus was also found in both adult and fetal rats, in which epithelial cells were also specifically stained. Altogether, our data show that VLA-4 is an additional component of the integrin repertoire of TEC, and suggest that it could have an important role in thymus epithelial cellthymocyte interactions.
Proceedings of The National Academy of Sciences, 1993
The signaling that causes the leukocyte integrin lymphocyte function-associated molecule (LFA-1) to bind firmly to its ligand intercellular adhesion molecule 1 (ICAM-1) is transduced indirectly through other T-cell receptors and is termed inside-out signaling. We show here that the highaffinity state of LFA-1 is characterized by expression of the LFA-1 epitope detected by monoclonal antibody 24. This epitope is expressed not in response to the initial agonistmediated signal but when LFA-1 binds to ICAM-1, indicating that ligand binding induces an alteration in LFA-1. As would be predicted, the monoclonal antibody 24 epitope is confined to the LFA-1, which is located at the site ofcontact between T cells and ICAM-1-expressing transfectants. When a fixation protocol for "freezing" receptors is used, only T cells that are fixed after prior exposure to ICAM-1 bind frmly to ICAM-1 a
Pnas, 1987
Considerable evidence now exists to support the notion that the 50-kDa sheep erythrocyte-binding protein, T1l, represents an essential cell surface component of a human T-cell lineage activation pathway. Furthermore, it is known that the human T3-Ti T-cell antigen/major histocompatibility complex receptor complex is capable of regulating cell growth mediated by the Til structure. Here we show that, within the T3' thymocyte compartment, T3-Ti crosslinking rapidly inhibits Til-initiated interleukin 2 (IL-2) gene transcription and translation. This inhibition is restricted to the IL-2 gene (IL2) as transcription of both the IL-2-receptor gene (JL2R) and the Ti fl-chain gene (TCRB) are not affected (human gene designations are in parentheses). Perhaps more importantly, T3-Timediated IL-2 inhibition of this type is not operational in peripheral T lymphocytes. The results imply that the majority of T3V thymocytes are functionally distinct from peripheral T lymphocytes despite their T3' phenotype and must possess a unique endogenous regulatory component for suppressing IL-2 gene activity. Moreover, since IL-2 is likely rate-limiting for growth within the thymus, the findings provide one plausible mechanism for thymic selection-namely, T3-Ti crosslinking of thymocytes upon interaction with self-major histocompatibility complex inhibits clonal expansion of high-affinity autoreactive cells.
The Journal of Immunology, 2006
Adhesion-and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, ␣ L  2 ). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I-and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgenebearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection.