B7+-transfectant tubular epithelial cells induce T cell anergy, ignorance or proliferation

Abstract

We have previously established that interferon (IFN)-γ stimulated, antigen-pulsed tubular epithelial cells (TEC) stimulate antigen (Ag) specific activation of T cell hybridomas to express IL-2. In contrast, these Ag pulsed TEC do not stimulate T helper 1 (Th1) clones to proliferate, but rather render them unresponsive, since Ag pulsed spleen cells cannot restore these cells to proliferate. The interaction of the T cell CD28 surface protein with its ligand B7 expressed on Ag presenting cells bearing Ia is a potent co- stimulatory signal capable of inducing T cell proliferation. Hence, the lack of B7 on TEC was hypothesized to be responsible for anergy in these Th1 cells. Therefore, the B7 gene was transfected into a SV40 transformed TEC or Chinese hamster ovary (CHO) cells, and created TEC and CHO cells expressing surface B7 protein. TEC-B7 (IFN-γ stimulated, Ag pulsed) express Ia and induce IL-2 production by T cell hybridomas. In contrast, T cell proliferation was not induced by TEC-B7 or CHO-B7 cells; however, these Th1 cells were not anergic since they could be stimulated to proliferate to Ag pulsed spleen cells (immunological ignorance). However, co-cultivating TEC- B7 (IFN-γ stimulated, Ag pulsed) with Th1 cells, stimulated through the T cell receptor (TCR) using anti-CD3 monoclonal antibody (mAb) caused these Th1 cells to proliferate. Furthermore, anti-CD28 and anti-B7 mAbs blocked this response. These data suggest that the spectrum of Th1 cell activation after encounter with Ag is dictated by: (1) the vigor of TCR/CD3 signal, and (2) presence or absence of co-stimulatory signals through the CD28 pathway. Since expression of Ia on TEC induces anergy, this may serve as a mechanism to thwart - not foster - autoimmunity.