Thymocyte Contact or Monoclonal Antibody-Mediated Clustering of 3β1 or 6β4 Integrins Activate Interleukin-6 (IL-6) Transcription Factors (NF-κB and NF-IL6) and IL-6 Production in Human Thymic Epithelial Cells

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3745-3755 ◽  
Author(s):  
Dunia Ramarli ◽  
Maria Teresa Scupoli ◽  
Emma Fiorini ◽  
Ornella Poffe ◽  
Monica Brentegani ◽  
...  

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. Functional studies performed with MoAbs anti-β1 and -β4 integrins showed that β1, and, to a much lower extent, β4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of 3, 6, β1, and β4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of MoAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-κB nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation.

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3745-3755 ◽  
Author(s):  
Dunia Ramarli ◽  
Maria Teresa Scupoli ◽  
Emma Fiorini ◽  
Ornella Poffe ◽  
Monica Brentegani ◽  
...  

Abstract 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. Functional studies performed with MoAbs anti-β1 and -β4 integrins showed that β1, and, to a much lower extent, β4 heterodimers are involved in the TEC-thymocyte adhesion. Thymocyte contact or MoAb-mediated ligation of 3, 6, β1, and β4 integrins was investigated as a potential inducer of intracellular signaling in TEC. Thymocyte adhesion or cross-linking of MoAbs bound to integrins clustered at the TEC/thymocyte contact sites led to activation of interleukin-6 (IL-6) gene transcription factors, namely NF-IL6 serine phosphorylation and NF-κB nuclear targeting, as well as to increased IL-6 secretion. We propose that integrin clustering occurring during TEC-thymocyte contacts modulates in TEC the gene expression of a cytokine involved in thymocyte growth and functional differentiation.


1991 ◽  
Vol 138 (1) ◽  
pp. 79-93 ◽  
Author(s):  
Sylvia Cohen-Kaminsky ◽  
Rose-Marie Delattre ◽  
Odile Devergne ◽  
Patricia Rouet ◽  
Dominique Gimond ◽  
...  

2000 ◽  
Vol 113 (1) ◽  
pp. 169-177
Author(s):  
M.T. Scupoli ◽  
E. Fiorini ◽  
P.C. Marchisio ◽  
O. Poffe ◽  
E. Tagliabue ◽  
...  

Inside the thymus, thymic epithelial cells and thymocytes show an interdependent relationship for their functional differentiation and development. As regards possible interdependency for their mutual survival, it is clear that lympho-epithelial adhesion can control the survival of developing thymocytes whereas the effects of lymphoid adhesion on epithelial cell survival have never been described. To address this issue, we performed co-cultures between normal human thymic epithelial cells (TEC) and a mature lymphoid T cell line (H9) or unfractionated thymocytes. TEC were induced to apoptosis by growth factor deprivation and the level of cell death was measured by flow cytometry. TEC stimulated by cell adhesion showed a significant reduced apoptosis when compared to the control and this phenomenon was associated with increased binding activity of NF-(kappa)B, as measured by gel shift analysis. The activation of NF-(kappa)B was necessary to promote survival, since its inhibition by acetyl salicylic acid prevented the promoting effect. The mAb-mediated crosslinking of (alpha)(3)(beta)(1) was considered as a potential inducer of TEC survival, since we have previously demonstrated that the engagement of this integrin was able to induce NF-(kappa)B activation in TEC. The crosslinking of (alpha)(3)(beta)(1), which clustered at the lympho-epithelial contact sites, partially reproduced the promoting activity of cell adhesion. These results highlight that lympho-epithelial adhesion can control the survival of thymic epithelial cells through an intracellular pathway which requires the activation of NF-(kappa)B and is triggered by integrins of the (beta)(1) family.


1994 ◽  
Vol 54 (1-2) ◽  
pp. 192
Author(s):  
A.P. Riviera ◽  
E. Bartoccioni ◽  
F. Scuderi ◽  
S. Gallucci ◽  
S. Papini ◽  
...  

1998 ◽  
Vol 86 (2) ◽  
pp. 182-189 ◽  
Author(s):  
Birte von Patay ◽  
Harald Loppnow ◽  
Janka Feindt ◽  
Bodo Kurz ◽  
Rolf Mentlein

2021 ◽  
Vol 11 ◽  
Author(s):  
Magali Irla

Thymic epithelial cells (TECs) provide essential clues for the proliferation, survival, migration, and differentiation of thymocytes. Recent advances in mouse and human have revealed that TECs constitute a highly heterogeneous cell population with distinct functional properties. Importantly, TECs are sensitive to thymic damages engendered by myeloablative conditioning regimen used for bone marrow transplantation. These detrimental effects on TECs delay de novo T-cell production, which can increase the risk of morbidity and mortality in many patients. Alike that TECs guide the development of thymocytes, reciprocally thymocytes control the differentiation and organization of TECs. These bidirectional interactions are referred to as thymic crosstalk. The tumor necrosis factor receptor superfamily (TNFRSF) member, receptor activator of nuclear factor kappa-B (RANK) and its cognate ligand RANKL have emerged as key players of the crosstalk between TECs and thymocytes. RANKL, mainly provided by positively selected CD4+ thymocytes and a subset of group 3 innate lymphoid cells, controls mTEC proliferation/differentiation and TEC regeneration. In this review, I discuss recent advances that have unraveled the high heterogeneity of TECs and the implication of the RANK-RANKL signaling axis in TEC differentiation and regeneration. Targeting this cell-signaling pathway opens novel therapeutic perspectives to recover TEC function and T-cell production.


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