Cardiac EC expressed comparative, easily detectable amounts of -gal in immunized and unimmunized TIE2-lacZ and VWF-lacZ mice but not in control FVB mice (Physique ?(Figure4A).4A). their blood vessels showed no histological abnormalities. In response to -gal em in vitro /em , CD4+ and CD8+ T cells from immunized transgenic and FVB mice proliferated, expressed CD25, and secreted IFN-. Contamination with Levalbuterol tartrate recombinant vaccinia computer virus encoding -gal raised equivalent responses in transgenic and FVB mice. Hearts transplanted from transgenic mice into FVB mice continued to beat and the graft EC continued to express -gal. These results suggested immunological ignorance of the transgene encoded EC protein. However, skin transplanted from TIE2-lacZ onto FVB mice lost -gal+ EC and the hosts developed -gal-specific antisera, demonstrating activation of host immune effector mechanisms. In contrast, skin grafted from TIE2-lacZ onto VWF-lacZ mice retained -gal+ EC and no antisera designed, suggesting a tolerant host immune system. Conclusion Resting, -gal+ EC in transgenic mice tolerize specific lymphocytes that would otherwise respond against -gal expressed by EC within transplanted skin. We conclude that EC effectively present intracellular “self” proteins to the immune system. However, antigen presentation by EC Levalbuterol tartrate does not delete or anergize a large population of specific lymphocytes that respond to the same protein following standard immunization with protein or expression vector DNA. These results clearly demonstrate striking context sensitivity in the immune acknowledgement of EC, a subtlety that must be better comprehended in order to treat immune diseases and complications involving the vasculature. Background Endothelial cells (EC) form the inner lining of blood vessels and are therefore uniquely situated between circulating lymphocytes and peripheral tissues. Vascular EC are thought to participate in the recruitment of T lymphocytes from your bloodstream into sites of contamination and inflammation [1,2]. After transplantation of vascularized, allogeneic tissues, EC are the first graft cells encountered by the host lymphocytes and may be important initiators and targets of allograft rejection [3,4]. T cells also protect against intracellular pathogens that infect EC, such as cytomegalovirus, em Chlamydia pneumoniae /em , rickettsia and hantavirus. Immune responses within the blood vessel wall are particularly important because chronic inflammation can lead to vascular remodeling and the development of arteriosclerosis . T cell antigen acknowledgement can lead to tolerance or aggression, depending on the developmental stage of the T cell and the precise interactions between the T cell and the antigen presenting cell (APC). T cell antigen receptors identify specific peptides bound to MHC molecules on the surface of the APC. Professional APC provide certain additional activities, collectively termed costimulation, that regulate and strengthen T cell Levalbuterol tartrate responses. Cell surface molecules and soluble proteins (chemokines, cytokines, and lymphokines) mediate costimulation. Professional APC express CD80 (B7-1) and related molecules, which act through CD28-related molecules on T cells. Professional APC also express CD40, which acts through CD154 (CD40 ligand) and is an essential mediator of collaboration between T cells [6-8]. EC have been termed “semiprofessional” APC because they costimulate certain T cell responses em in vitro /em and because they are thought to stimulate alloresponses em in vivo /em [9-13]. EC cultured from different vascular beds can act as APC em in vitro /em . For example, EC cultured from human umbilical veins (HUVEC), pulmonary arteries, iliac arteries and veins, and murine lung EC all costimulated T cells treated with mitogens, generating stronger proliferation and IL-2 secretion [9,14-20]. In contrast, vascular smooth muscle cells do not provide costimulation . Human EC express CD40, CD58 (LFA-3), CD134 (OX40) ligand and ICOS ligand, which can contribute to T cell activation em in vitro /em [21-23]. HUVEC do not express CD80 and they cannot stimulate na?ve T cells em in vitro /em . Although murine lung microvascular EC do express CD80, they costimulated only memory T cells em in vitro /em . Mouse liver Levalbuterol tartrate sinusoidal EC express CD80 and other costimulatory molecules but they are reported to induce antigen specific tolerance em in vitro /em . In contrast, murine aortic EC can stimulate em in vitro /em naive T cells expressing alloreactive antigen receptor transgenes . Thus, EC costimulation properties em in vitro /em may differ depending upon the antigen, the species, the maturity of the T cell, and the vascular bed of origin. EC activities as APC em in vitro /em may be poor indicators of their activities em in vivo /em because cells change upon isolation and culture. For example, although human EC strongly express MHC Rabbit Polyclonal to TNFRSF6B class I and class II molecules em in vivo /em , MHC class I expression is reduced and class.