Human endothelial stimulation of allogeneic T cells via a CTLA-4 independent pathway.
It is accepted that T cells require at least two signals to undergo proliferation and cytokine release: an antigen dependent signal mediated via the the TCR (T cell receptor) and an antigen independent signal mediated via one or more accessory or adhesion molecules. Interaction between CD28 or CTLA-4 and the B7 co-receptors found on many antigen presenting cells (APC) is known to be essential for antigen specific (including alloantigen) expansion of T cells in vitro and in vivo. CTLA-4-Ig is a fusion protein with very high affinity for B7. It has been used in vivo to block both allograft and xenograft rejection. Most of the work investigating second signal requirement has used 'professional' APC. In view of the observations that class II positive human endothelial cells can cause direct allostimulation of resting CD4+ and CD8+ T cells, we have investigated the requirement of CTLA-4 in this response. The current studies show that the proliferative response of allogeneic CD4+ and CD8+ T cells to interferon-gamma treated HUVEC (human umbilical vein endothelial cells) is inhibited by monoclonal antibodies (mAbs) against MHC class II and class I antigens, respectively, but not by CTLA-4-Ig. In contrast, lymphocytes proliferating in response to allogeneic splenocytes are inhibited by CTLA-4-Ig. Cell surface binding studies using flow cytometry demonstrated failure of endothelial cells to bind either CTLA-4-Ig or mAbs against B7 receptors. In conclusion, different APC use different co-stimulatory signals. The possibility that this leads to different cytokine profiles needs to be investigated to further understand the role of endothelial cells in transplant rejection.
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Department of Cardiac Surgery, National Heart and Lung Institute, Harefield Hospital, Middlesex, UK.
Thompson
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Yacoub
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Rose
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D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology*; D018122:B7-1 Antigen / Q000502:physiology; D060908:CTLA-4 Antigen; D002460:Cell Line; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept; D007371:Interferon-gamma