CD27-mediated immune suppression by HSPCs, innate immune cells or non-hematopoietic cells

Project Summary Hematopoietic stem and progenitor cells (HSPCs) are well documented to give rise to various lineages of innate and adaptive immune cells. The CD27-CD70 pair belong to the Tumor Necrosis Factor (TNF) superfamily. Aside from mounting publications showing the roles of this pathway in T cell, B cell and NK cell function, a limited number of studies have demonstrated that CD27 is highly expressed in HSPCs. Previous studies have demonstrated that the CD27-CD70 pathway plays an important role in the interface between HSPCs and mature immune cells, whereby CD27-CD70 interaction modulates the differentiation of hematopoietic stem cells into mature blood cell lineages during immune activation. To selectively study CD27 function in HSPCs, we have developed an innovative genetic reductionist model based on Rag1 KO mice (deficient for B and T cells) supplemented with NK cell depletion, in which only HSPCs are known to express CD27. We have used these mice as hosts for allogeneic hematopoietic cell transplantation (allo-HCT) to study graft-versus-host disease (GVHD). Our preliminary results demonstrate that Rag1-CD27 double KO (DKO) mice developed more severe GVHD compared to Rag1 KO mice, strongly suggest that host-type HSPCs can use CD27 to directly inhibit allogeneic T cell activation and/or function, thereby suppressing the development of GVHD. Remarkably, these results reveal that stem cell-expressed CD27 is not only a cell surface receptor that responds to inflammatory signal (CD70) to modulate stem cells towards lineage differentiation, but can also directly deliver an inhibitory signal to overactive T cells, thereby counteracting inflammation and maintaining homeostasis. Therefore, we hypothesize that HSPCs possess a previously unknown direct immune checking function that is mediated through the CD27-CD70 pathway. We postulate that this direct immune suppressive mechanism by HSPCs may provide a critical line of protection against overactive lymphocytes, and is important for the maintenance of a homeostatic environment for HSPCs to preserve the longevity of the foundation of the hematopoietic system. Furthermore, this direct immune checking function of HSPCs may be exploited and enhanced to improve the treatment of immunological disorders. In parallel, we will test an alternative hypothesis that previously unidentified innate immune cells or non-hematopoietic cells may activate CD27 to suppress inflammatory T cell response. In this proposal, we will study this pathway in the unique setting of stem cell biology, immunobiology, allo-HCT, immune reconstitution and GVHD. Aim 1 will determine the CD27-dependent immune suppressive feature of HSPCs in vivo and in vitro. Aim 2 will characterize previously unidentified innate immune cells or non- hematopoietic cells that possess CD27-dependent immune suppressive function. This proposal is useful for understanding the mechanisms of immunologic diseases, and may provide a novel avenue to enhance the therapeutic application of stem cells in immunological disorders, and thereby improving treatment outcome and quality of life for patients with immunologic diseases.