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In View: Game Changer

Myeloid Cell Memory via PIR-A: A Game Changer in Allograft Rejection Cascade?

Kojima, Hidenobu MD, PhD1; Kupiec-Weglinski, Jerzy W. MD, PhD1

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doi: 10.1097/TP.0000000000003358
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By definition, immunological memory has been associated with adaptive immune cell repertoires, such as T and B lymphocytes and evidenced by specific immune responses to previously encountered alloantigens. While recent studies have addressed innate immune memory in monocytes and macrophages, referred to as “trained immunity,” such a response has been considered nonspecific and distinct from conventional immunological memory.1 Whether innate myeloid cells can memorize antigens for specific immune response, like adaptive immune cells do, remained unknown until a recent report in Science from the Pittsburgh and Houston transplant research groups. Indeed, Dai et al provide evidence that innate myeloid cells may acquire alloantigen-specific memory, which could be then targeted to attenuate allograft rejection.2 The authors show that mouse monocytes and macrophages acquire immunological memory specific to major histocompatibility complex (MHC)-I antigen and identified paired immunoglobulin-like receptors-A (PIR-A) as the MHC-I binding partners necessary to mount memory responses. These findings introduce PIR-A as putative therapeutic target for allograft rejection (Figure 1).

FIGURE 1.
FIGURE 1.:
PIR-A and PIR-B signaling. PIR-A deliver stimulatory signals via FcRγ on ITAM, and PIR-B transmits inhibitory signals via multiple cytoplasmic ITIM by MHC-I molecules binding PIR-A/B. In the absence of PIR-B, PIR-A pathway activates APCs such as macrophages and DCs, and drives M1 phenotype. PIR-B can interact with MHC-I molecules in the same cell (cis interaction) in addition to recognizing MHC-I molecules in the neighbor cell (trans interaction), leading to competitive blocking access of CD8 molecules to MHC-I and regulating the activation of cytotoxic T cells. Besides these mechanisms, newly discovered monocyte and macrophage memory via PIR-A might regulate allograft survival including long-term outcomes. APC, antigen-presenting cells; DCs, dendritic cells; FcRγ, Fc receptor common γ chain; ITAM, immunoreceptor tyrosine-based activation motifs; ITIM, immunoreceptor tyrosine-based inhibitory motifs; MHC, major histocompatibility complex; PIR, paired immunoglobulin-like receptors; TCR, T-cell receptor.

PIR-A3/Fc, which blocks PIR-A3 from binding to MHC-I ligand (H-2Dd), inhibited both macrophage and monocyte memory response in BALB/c (H-2d)-immunized mice. On the other hand, PIR-A3/Fc failed to suppress memory responses of monocytes to C3H (H-2k)-immunized recipients, suggesting that PIR-A3 crosstalk was MHC-I antigen specific. The elimination of monocyte memory response was then confirmed in a PIR-A knockout mouse system. These results indicate that PIR-A is essential to evoke antigen-specific memory response in murine innate myeloid cells.

The authors also present mouse data from well-defined kidney and heart allograft models. When BALB/c kidneys were transplanted to wild type, Pira−/−, or Pirb−/− C57BL/6 recipients, acute allograft rejection was not observed in wild type and Pira−/− mice; however, allografts were rejected promptly in Pirb−/− hosts. Notably, when treated with PIR-A3/Fc, Pirb−/− recipients did not experience allograft rejection. These findings imply that PIR-B prevents allograft rejection while PIR-A accelerates alloimmunity in the absence of PIR-B signaling. In addition, chronic rejection was significantly attenuated in Pira−/− mice and in Pirb−/− mice treated with PIR-A3/Fc. Moreover, the combinatorial treatment with PIR-A3/Fc and CTLA4-Ig prevented acute and chronic rejection of cardiac allografts. These results are consistent with the hypothesis that inhibition of PIR-A pathway can mitigate the allograft rejection cascade, including chronic rejection, via a new mechanism of antigen-specific monocyte/macrophage memory.

The immunosuppressive drug development has largely focused on targeting host adaptive immunity with current strategies concentrating on adjunctive therapies, which include calcineurin inhibitors, to inhibit T-cell activation. However, despite reduced incidence of acute rejection and improved short-term clinical outcomes, current therapies largely fail to benefit long-term graft survival due to ensuing chronic rejection.3 The remarkable new finding by Dai et al is not only documenting that the PIR-A pathway mediates antigen-specific memory in monocytes and macrophages but also offers a novel mechanism of chronic graft rejection, the key reason of transplant failure nowadays. This discovery might also represent a paradigm shift in the ongoing quest to develop more selective yet effective immunosuppressive drugs for transplant recipients.

Another important issue is to minimize immunosuppressive drugs toxicity as currently used agents cause severe adverse side effects, such as metabolic diseases, infections, and cancers. Although adjunctive immunosuppressive regimens aim at blocking alloimmune responses with less toxicity, new therapeutic concepts to reduce adverse effects while improving long-term graft survival and clinical outcomes are warranted. Of note, chronic rejection was reduced in Pira−/− mice possibly due to inhibition of memory responses in monocytes and macrophages, whereas Pira−/− mice retained primary response and functions of innate immune cells. This finding suggests at least a partial allospecificity of the PIR-A pathway offering the opportunity to selectively affect allograft rejection with less toxicity.

PIR-A and PIR-B are expressed on B cells and myeloid cells but not on T cells or natural killer cells.4 Stimulatory function of PIR-A and inhibitory function of PIR-B have been reported. PIR-B as an MHC-I receptor can regulate the activation of cytotoxic T cells by competitively blocking access of CD8 molecules to MHC-I while controlling B cells and myeloid cells via inhibitory signals.5Pirb−/− mice have shown accelerated graft-versus-host disease with augmented activation of recipient dendritic cells, concomitant to an upregulation of PIR-A.6 The balance between PIR-A and PIR-B was reported to regulate the differentiation of macrophages into M1 or M2 phenotypes as well.7 Moreover, there might be complex interactions between PIR-A and PIR-B in the allograft rejection cascade. Further evaluations are thus required for PIR-A inhibition as to (1) whether and how B cells expressing PIRs are involved in allograft rejection; (2) to understand detailed mechanisms besides suppressing myeloid cell memory; and (3) to recognize possible adverse effects.

The limitation of the study is the lack of clinical data. Although leukocyte immunoglobulin-like receptors (LILRs) in humans are orthologs of PIRs in mouse, there are some differences between PIRs and LILRs. For example, unlike PIR-B, LILR-B1 is expressed on natural killer and T lymphocytes in addition to B cells and myeloid cells.8 Further, some ligands for LILR-A/B still remain to be elucidated. Hence, future studies should confirm whether LILR-A can mediate antigen-specific memory of myeloid cells and be a target for allograft rejection in humans.

Clearly, the demonstration of antigen-specific memory in innate immune cells is a stunning and novel finding. Long-term graft survival by inhibiting PIR-A signaling that mediates myeloid cell memory is a notable new finding as well. Validation of these findings in human transplant patients is warranted. Along with further research, this new pathway could be a game changer to uncover underlying mechanisms in chronic rejection, and possibly to acquire long-term tolerance, an unfulfilled holy-grail in organ transplantation. Of note, patients with malignant or autoimmune diseases might benefit from this signaling pathway as well.

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