Innate NK Cells and Macrophages Recognize and Reject Allogeneic Nonself In Vivo via Different Mechanisms

Abstract

Both innate and adaptive immune cells are involved in the allograft response. But how the innate immune cells respond to allotransplants remains poorly defined. In the present study, we examined the role of NK cells and macrophages in recognizing and rejecting allogeneic cells in vivo. We found that in naïve mice NK cells are the primary effector cells in killing of allogeneic cells via “the missing self” recognition. However, in alloantigen pre-sensitized mice, NK cells are dispensable. Instead, macrophages become alloreactive and readily recognize and reject allogeneic non-self. This effect requires help from activated CD4+ T cells and involves CD40/CD40L engagement, as blocking CD40/CD40L interactions prevents macrophage mediated rejection of allogeneic cells. Conversely, actively stimulating CD40 triggers macrophage-mediated rejection in the absence of CD4+ T cells. Importantly, alloantigen primed and CD4+ T cell-helped macrophages (licensed macrophages) exhibit potent regulatory function in vivo in an acute GVHD model. Together, our data uncover an important role for macrophages in the alloimmune response and may have important clinical implications.

The Evolving Roles of Memory Immune Cells in Transplantation

“…Consequently, the memory pool differs among individuals due to differences in immune history, pathogen exposures, and age. Memory cells are traditionally believed to be key features of adaptive immune cells (i.e., T cells and B cells), but recent studies have challenged this belief and further suggested that certain innate immune cells, such as NK cells and macrophages, can also acquire certain memory properties(1,2), a finding that is of great significance in transplantation.…”

“…However, recent studies suggest that certain types of innate immune cells, such as NK cells and macrophages, can also acquire memory features in that they can mediate robust recall responses. (1,2) Furthermore, in certain transplant models, subsets of memory cells have been recently shown to function as regulatory cells, and contrary to the initial belief, such memory T cells actually promote transplant survival. (3,4) Additionally, not all memory cells are committed to memory functions at all times.…”

Origin and Biology of the Allogeneic Response

“…This form of allorecognition may initiate or amplify the responses of recipient T cells to MHC and mHAg alloantigens by inducing the maturation of APCs. It could also provide phagocytic cells with the means to kill allogeneic targets without inflicting damage on self-tissues (Liu et al 2012). The ubiquity of allorecognition phenomena among sessile, colonial marine animals tempts one to speculate that mammalian innate allorecognition originated in invertebrate ancestors that routinely engaged in conspecific interactions in their natural habitats (Dishaw and Litman 2009).…”

Role of IL-21 signaling pathway in transplant-related biology

“…To date, it is known that IL-21 is primarily produced by natural killer T (NKT) cells and CD4 + T cells and has various activities on multilineages such as B-and T-cells, NKT cells, natural killer (NK) cells, and bone marrow-derived dendritic cells (BMDCs) [9]. Since both innate and adaptive immune cells contribute to allograft responses including T-and B-cells, NK cells, and macrophages in organ transplantation [10], it is conceivable that IL-21 and its receptor (IL-21R) are closely associated with transplant tolerance induction. Herein, our present article is the first to describe role of IL-21 signaling pathway in transplantrelated biology for better understanding.…”