Innate Myeloid Cells Remember and Reject Allogeneic Nonself in Transplantation

Abstract

Li comments on the discovery of PIR-A in donor-specific myeloid cell memory in transplantation. Li comments on the discovery of PIR-A in donor-specific myeloid cell memory in transplantation. CITATIONS Dai H, Lan P, Zhao D, et al. PIRs mediate innate myeloid cell memory to nonself MHC molecules. Science. 2020;368:1122–1127. Memory is a cardinal feature of the immune system and is traditionally ascribed to cells in the adaptive arm (i.e., T and B cells). Recent studies suggest that innate natural killer (NK) cells, macrophages and innate lymphoid cells (ILCs) can also acquire features of “memory” and become capable of mounting a “secondary” response against invading pathogens. In most cases, however, those enhanced secondary responses are not necessarily antigen specific but rather represent a state of epigenetic and metabolic reprogramming of such innate cells acquired in the primary responses. A recent paper in Science by Dai et al. demonstrated in a mouse model that innate monocytes and macrophages can develop into memory cells that exhibit exquisite donor antigen specificity; they require donor alloantigen presensitization for their induction and are involved in the rejection of kidney and heart allografts. Importantly, the authors identify paired Ig-like receptor-A (PIR-A) as MHC class I–binding receptors that mediate donor-specific myeloid cell memory. The studies are extensive but can be broken down into three parts for the purpose of this discussion: (a) induction of memory myeloid cells (monocytes and macrophages) that are donor antigen specific, (b) identification of PIR-A as donor MHC class I–specific receptors that mediate myeloid cell memory, and (c) the role of PIR-A in triggering the rejection of kidney and heart allografts in mice. The basic approach that generates the memory monocytes and macrophages involves presensitization of the Rag−/−Il2rg−/− mice (H-2b), which are deficient in T, B, and NK cells, as well as ILCs, with allogenic BALB/c cells (H-2d). Challenge of these presensitized mice showed that monocytes and macrophages only respond to the donor antigens to which they are sensitized, but not the third-party antigens. In this secondary response, monocytes recognize donor BALB/c antigens and transform into dendritic cells to prime for rejection, whereas macrophages specifically recognize and kill donor cells. None of those activities occurred in the absence of donor antigen presensitization, nor did they occur after sensitization with syngeneic C57BL/6 cells. This state of donor antigen specificity and memory is also observed when the Rag−/−Il2rg−/− mice were presensitized with C3H (H-2k) or NOD (H-2g7) cells. Importantly, this type of specific memory can be passively transferred by monocytes and macrophages from the presensitized Rag−/−Il2rg−/− hosts to naïve ones, thus demonstrating the role of monocytes and macrophages in mediating donor-specific myeloid cell memory. Further studies using the MHC congenic mice, MHC class I–deficient mice, and the MHC class I–binding tetramers led to the subsequent revelation of donor-specific MHC class I molecules in the induction of myeloid cell memory. The identification of PIR-A as receptors for donor MHC class I molecules mediating the memory monocytes and macrophages, which involved the use of multiple approaches and cutting-edge technologies, is significant. PIR is the ortholog of human leukocyte Ig-like receptor (LILR), and consists of PIR-A and PIR-B. PIR-A is highly polymorphic, consists of at least six isoforms and transmits activating signals, while PIR-B is nonpolymorphic and triggers inhibitory signals. The authors showed in scRNA-seq and Pira reporter systems that PIR-A3 is the predominant isoform that engages donor class I molecules; they further showed that treatment of the presensitized Rag−/−Il2rg−/− hosts with PIR-A3/Fc, a fusion protein that blocks donor class I molecules, inhibited donor-specific myeloid cell memory. Finally, in models of kidney and heart transplants, genetic deletion of Pira or treatment with the PIR-A3/Fc inhibited chronic rejection and markedly prolonged graft survival, suggesting that this pathway is involved in rejection and can be therapeutically targeted to promote graft survival. Clearly, the finding that innate myeloid cells can acquire donor-specific memory is exciting, and the involvement of these cells in chronic allograft rejection is significant. However, the studies by Dai et al. are exclusively in mice, and further inquiries into human myeloid cells, investigating whether they also acquire features similar to those of their mouse counterparts in transplant settings, will be paramount in moving the field forward. Xian C. Li, MD, PhD is professor and director at the Immunobiology and Transplant Science Center and Department of Surgery at Houston Methodist Hospital in Texas.