Bat-mouse bone marrow chimera: a novel animal model for dissecting the uniqueness of the bat immune system

Yong, Kylie Su Mei; Ng, Justin Han Jia; Her, Zhisheng; Hey, Ying Ying; Tan, Sue Yee; Tan, Wilson Wei Sheng; Irac, Sergio Erdal; Liu, Min; Chan, Xue Ying; Gunawan, Merry; Foo, Randy Jee Hiang; Low, Dolyce Hong Wen; Mendenhall, Ian Hewitt; Chionh, Yok Teng; Dutertre, Charles-Antoine; Chen, Qingfeng; Wang, Lin-Fa

In addition to the successful reconstitution of bat immune cells in mice, this study also revealed an important, and unexpected, discovery that successful engraftment of mature immune cell xenograft can be achieved with no signs of clinical abnormalities. First of all, based on the results of engrafting mature splenocytes in mice, it is possible that mature immune cells in bats, such as monocytes, T/NK, B cells and DCs have some long-lived recirculating and expansion ability. However, we cannot rule out the possibility that reconstitution by rare recirculating stem cells or progenitors may occur. This interesting hypothesis is worth further investigation to examine possible new insights into unusual mechanisms for mature cell renewal and reprogramming in bats. Secondly, observed resistance to rejection is noteworthy and may suggest that transplantation of mature bat immune cells into hosts which are not necessarily genetically and MHC matched might not lead to rejection. In order to generate a graft rejection response, 3 key players need to be present, an antigen source, functional T cells and antigen presenting cells from the host. The lack of graft rejection symptoms can be attributed to multiple reasons, one of the main concern is can bat T cells recognise murine MHC molecules and other co-stimulatory molecules. Bat T cells could be primed to recognise the murine antigen via bat MHC molecules on bat antigen-presenting cells (APC), but the inability to recognise murine MHC molecules will prohibit the mounting of an immune response against host cells. Detailed characterisation of the bat major histocompatibility complex class I (MHC-I) molecules revealed unique peptide binding grooves not observed in any other mammals 58 . The hypothesized unique bat MHC-I molecule 58 could potentially contribute to the development of a T cell receptor (TCR) with different molecular structure on bat CD8 + T cells during positive selection in thymus. Hence, the bat TCR could lack the ability to recognise murine MHC-I molecules and thus, develop a compromised cytotoxic T lymphocytes response. However, these are speculations that require further investigation, which is not within the scope of this pilot, proof-of-concept study. The new model serves as a useful tool to explore deeper mechanisms on how bat immune cells develop resistance to graft rejection in the bat-mouse model while maintaining their functionality. This research would not only benefit the study of graft rejection, but also aid in the development of drugs used to curtail undesirable effects of transplantations.