Discovery and characteristics of endowed immunity
Dai et al. 46 showed that mice monocytes/macrophages can acquire an alloantigen-specific memory in response to secondary encounters, and identified that paired immunoglobulin-like receptor-A (PIR-A), a major histocompatibility complex (MHC)-I receptor, was necessary for the induction of macrophage memory. Either deleting PIR-A or blocking the PIR-A-MHC-I combination was demonstrated to suppress memory and attenuate the allograft rejection in kidney and heart transplantation. Similarly, Liu et al. 47 have reported that during secondary challenge, macrophages have the capacity to recognize and reject allogeneic antigens, which requires two signals, namely, priming with allogeneic antigens and the assistance of CD4+T cells. Chu et al. 48 also showed that macrophages primed with allogeneic antigens mounted an acute response to skin allografts with a certain degree of antigen specificity, which is similar to the characteristics of adaptive immune cells. The authors demonstrated that immunodeficient recipient mice showed no signs of rejection to allogeneic skin grafts, which is consistent with the findings of previous studies that have established that innate immune cells alone are insufficient to facilitate the rejection of allogeneic organ grafts. However, they found that immunodeficient recipient mice, which received antigen-immunized macrophages (primed macrophages) from immunocompetent mice, were able to efficiently reject the same allogeneic skin grafts, although not third-party skin grafts, or showed significantly slower rejections of the grafts. In summary, when primed macrophages in immunocompetent mice are exposed to the same allogeneic antigen secondarily, primed macrophages undergo pronounced proliferation, expand during the immune response and exert a direct graft-rejection effect, at least partially, via a perforin-dependent pathway.
In addition, the assistance of helper CD4+T cells, but not CD8+T cells, during the priming period was found to be essential for naïve macrophages to gain the ability to distinguish allografts and thus promote rejection 48-50. In a follow-up study, the same authors reported that the specific memory of primed macrophages in the rejection of allogeneic cells and skin grafts was long-term and persisted for at least 4 months (until the end of the experimental period) 51. In conclusion, macrophages can become endowed with memory that facilitates the recognition of allogeneic antigens or specific molecules, and thereby induce an inflammatory response on secondary encounter. Accordingly, suppressing this memory may represent a potential therapeutic strategy for improving transplantation outcomes. However, in a study of mouse alveolar macrophages, Yao et al. 52 found that the induction of macrophage memory after respiratory viral infection required the assistance of effector CD8+ T cells, but not CD4+ T cells.
Taken together, the findings of the aforementioned studies indicate that functional endowed immunity may require the assistance of different types of T cells in different disease models. Hence, further studies are needed to determine which T cell subsets facilitate the induction of macrophage memory under different conditions. Although endowed immunity may be associated with the secretion of inflammatory effectors and amplified adaptive immune responses 45, 53, the precise nature of the underlying molecular mechanisms remain unclear and necessitate further study.