Renal Tubular Epithelial Expression of the Costimulatory Molecule B7RP-1 (Inducible Costimulator Ligand)

Abstract

Abstract. MHC class II-expressing renal tubular epithelial cells (TEC) are able to present foreign peptide antigens to T cells. The costimulatory signals that are required for effective T cell activation upon antigen presentation by TEC have not been characterized. Various cultured TEC lines were examined for expression of the recently described costimulatory molecule B7RP-1 (B7h), a ligand of the T cell molecule inducible costimulator (ICOS), and expression was compared with that of B7.1, B7.2, and CD40. B7RP-1 and CD40 were abundantly expressed by cultured murine and human TEC, whereas B7.1 and B7.2 could not be detected. Stimulation with lipopolysaccharide or tumor necrosis factor-␣ did not induce B7.1 or B7.2 expression and did not alter B7RP-1 expression. Interestingly, interleukin-2 production by T cell hybridomas after antigen presentation by TEC was enhanced by blocking antibodies to B7RP-1 and ICOS. In contrast, blocking antibodies to B7RP-1 or ICOS exerted inhibitory effects on anti-CD3-activated murine splenocyte proliferation. Immunohistochemical staining of normal human kidneys demonstrated strong constitutive B7RP-1 expression in distal tubules, collecting ducts, and urothelium. In human kidneys with allograft rejection or interstitial nephritis, distinct B7RP-1 staining was also detected in proximal tubules, in areas of mononuclear infiltration. In conclusion, the B7RP-1/ICOS pathway negatively regulates T cell activation upon MHC class II-restricted antigen presentation by TEC. Because B7RP-1 is also expressed by tubules in vivo, it can be speculated that the B7RP-1/ICOS pathway could play an inhibitory role in TEC-mediated immune activation in the kidney.Renal proximal tubular epithelial cells (TEC) play an important role in the pathogenesis of immune renal injury, both as initiators of T cell responses and as targets of T cells. Various studies, including our own, have demonstrated that TEC express MHC class II antigens, particularly in response to interferon-␥ (IFN-␥) (1-3). TEC also have the ability to ingest and process antigen in the lysosomal compartment, then presenting it in the form of small antigenic peptides, in the context of MHC class II molecules, to CD4 ϩ T cells (3-5). Specific CD4 ϩ T cells may recognize antigen via T cell receptors. Various signaling pathways are then activated, transmitting the so-called signal 1 to the interior of the T cells (6).Typical antigen-presenting cells initiate a second signal (signal 2), which is needed to fully activate the T cells. This second signal is usually received by T cells through the interaction of CD28 with B7 (7). Several studies have demonstrated, however, that cultured TEC lack the classic B7 molecules, including B7.1 and B7.2. Furthermore, B7.1 and B7.2 are not observed on tubules in vivo, in animal models of renal injury (8 -10). This has raised many questions regarding the nature and importance of signal 2 in the interaction of T cells with TEC.Ligation of T cell receptors in the absence of signal 2 may result in clonal anergy (11...

ICOS Ligation Recruits the p50α PI3K Regulatory Subunit to the Immunological Synapse

“…In contrast to CD28 that predominantly acts during the primary response, ICOS plays a role in restimulation and clonal expansion of T and B effector cells during secondary responses. ICOS, whose expression has been described not only on freshly activated T cells, but also on regulatory and memory T cells, can interact with its ligand on non-professional and nonhematopoietic APCs such as epithelial or endothelial cells under pro-inflammatory conditions (46,47). ICOS ligation in inflamed peripheral tissues could thus induce a sustained PI3K activation thereby regulating T cell energy metabolism and allowing quick and efficient responses to Ag restimulation (48).…”

Cellular pathophysiology of ischemic acute kidney injury

“…In addition to its role in generating mediators that contribute to the inflammatory response, the proximal tubular epithelium expresses MHC II and therefore can present antigen to T cells and express costimulatory molecules (40). Proximal tubule cells respond to T cell ligands through activation of cell surface receptors (41).…”

Inducible Co-Stimulator Null MRL-Fas lpr Mice

“…ICOS-L is more broadly expressed than B7-1 and B7-2. ICOS-L is expressed on professional APC (including dendritic and B cells) and parenchymal cells such as endothelial and epithelial cells, most notably, renal tubular epithelial cells (TEC) (25)(26)(27)(28).…”