B7x in the Periphery Abrogates Pancreas-Specific Damage Mediated by Self-reactive CD8 T Cells

Abstract

B7x (B7-H4 or B7S1) is the seventh member of the B7 family and the in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. Here we showed that B7x protein was not detected on antigen-presenting cells or T cells in both human and mice, which is unique in the B7 family. As B7x protein is expressed in some peripheral cells such as pancreatic β cells, we utilized a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-antigen, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ mice and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

“…Similar to previous reports, murine B7-H4 was detected in the islet cells of the pancreas 16,21,22 and the epithelial lining of the lung. 21 Additionally, we uncovered previously unrecognized expression in the esophagus, trachea, salivary gland, mammary, gallbladder, liver, kidney, uterus, and haired skin (Figure 4).…”

“…18 Several groups were unable to detect B7-H4 protein in immune cells in vitro, 16,21,22 despite early studies that reported expression. 10,11 Murine B7-H4 protein is detectable in pancreatic islet cells 16,21,22 and in epithelial cells lining the lung, 21 however, expression in other organs has not been reported. Therefore, we developed an immunohistochemistry (IHC) protocol utilizing a novel B7-H4 antibody (AMP6H3).…”

“…20 Additionally, use of an anti-B7-H4 antibodydrug conjugate did not result in toxicity in preclinical models, suggesting that B7-H4-targeted therapy could be applied safely. Reports describing B7-H4 protein expression in normal murine tissues are limited, 16,21,22 warranting further examination. Surface B7-H4 protein binds a currently unknown receptor(s) on activated T cells that results in inhibition of T cell effector function via cell cycle arrest, 9 decreased proliferation, 9-11 and reduced IL-2 production [9][10][11] in vitro.…”

“…In addition to B7-H4's extrinsic effects on the immune system, tumor cells expressing B7-H4 demonstrate augmented tumor cell proliferation, 23,24 superior antiapoptotic ability, 12 and increased tumor growth even in the absence of a competent immune system. 12,23,24 Preclinical models of autoimmunity, 16,22,25 infection, 21,26,27 and cancer 28,29 implicate B7-H4 as a negative immune regulator of T cells, neutrophils, and myeloid-derived suppressor cells. However, questions about the functional role of B7-H4 in the tumor microenvironment exist as recent studies suggest a positive or bystander role for B7-H4 in spontaneous tumor development.…”

Emerging Targets in Cancer Immunotherapy: Beyond CTLA-4 and PD-1

“…It inhibits CD4 and CD8 cell proliferation and cytokine production [53]. It is hardly expressed on professional APC but is expressed on nonlymphoid tissues, mainly epithelial tissues where a role in immune tolerance is postulated [54,[56][57][58]. It is expressed in the lung epithelium and is implicated in attenuating the immune response to bacterial infection in mice [56].…”