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The pathophysiological importance of the immunogenicity of damage‐associated molecular patterns (DAMPs) has been pinpointed by their identification as triggers of allograft rejection following release from dying cells, such as after ischemia–reperfusion injury. In cancers, however, this strong trigger of a specific immune response gives rise to the success of cancer immunotherapy. Here, we review the recently literature on the pathophysiological importance of DAMPrelease and discuss the implications of these processes for allograft rejection and cancer immunotherapy, revealing a striking mechanistic overlap. We conclude that these two fields share a common mechanistic basis of regulated necrosis and inflammation, the molecular characterization of which may be helpful for both oncologists and the transplant community. Damage‐associated molecular patterns are released from both allografts and cancer cells, thereby stimulating immune cells in an astonishingly similar fashion.

Facial transplantation is a life‐changing procedure for patients with severe composite facial defects. However, skin is the most immunogenic of all transplants, and better understanding of the immunological processes after facial transplantation is of paramount importance. Here, we describe six patients who underwent full facial transplantation at our institution, with a mean follow‐up of 2.7 years. Seum, peripheral blood mononuclear cells, and skin biopsy specimens were collected prospectively, and a detailed characterization of their immune response (51 time points) was performed, defining 47 immune cell subsets, 24 serum cytokines, anti‐HLAantibodies, and donor alloreactivity on each sample, producing 4269 data points. In a nonrejecting state, patients had a predominant T helper 2 cell phenotype in the blood. All patients developed at least one episode of acute cellular rejection, which was characterized by increases in interferon‐γ/interleukin‐17–producing cells in peripheral blood and in the allograft's skin. Serum monocyte chemotactic protein‐1 level was significantly increased during rejection compared with prerejection time points. None of the patients developed de novodonor‐specific antibodies, despite a fourfold expansion in T follicular helper cells at 1 year posttransplantation. In sum, facial transplantation is frequently complicated by a codominant interferon‐γ/interleukin‐17–mediated acute cellular rejection process. Despite that, medium‐term outcomes are promising with no evidence of de novodonor‐specific antibody development. In this study, the authors characterize the immune responses of six patients who underwent face transplantation and find that an increase in both IFN‐γ/IL‐17–producing cells in peripheral blood and in the allograft's skin with a concomitant peak in serum MCP‐1 levels and a reduction in circulating Th2 cells characterizes acute cellular rejection.

We have shown that CD39 and CD73 are coexpressed on the surface of murine CD4+Foxp3+regulatory T cells (Treg) and generate extracellular adenosine, contributing to Treg immunosuppressive activity. We now describe that CD39, independently of CD73, is expressed by a subset of blood‐derived human CD4+CD25+CD127lo Treg, defined by robust expression of Foxp3. A further distinct population of CD4+CD39+T lymphocytes can be identified, which do not express CD25 and FoxP3 and exhibit the memory effector cellular phenotype. Differential expression of CD25 and CD39 on circulating CD4+T cells distinguishes between Treg and pathogenic cellular populations that secrete proinflammatory cytokines such as IFNγ and IL‐17. These latter cell populations are increased, with a concomitant decrease in the CD4+CD25+CD39+Tregs, in the peripheral blood of patients with renal allograft rejection. We conclude that the ectonucleotidase CD39 is a useful and dynamic lymphocytes surface marker that can be used to identify different peripheral blood T cell‐populations to allow tracking of these in health and disease, as in renal allograft rejection.

Foxp3regulatory T cells (Tregs) express both ectoenzymes CD39 and CD73, which in tandem hydrolyze pericellular ATP into adenosine, an immunoinhibitory molecule that contributes to Treg suppressive function. Using Foxp3GFP knockin mice, we noted that the mouse CD4CD39T-cell pool contains two roughly equal size Foxp3and Foxp3?populations. While Foxp3CD39cells are CD73brightand are the bone fideTregs, Foxp3?CD39cells do not have suppressive activity and are CD44CD62L?CD25?CD73dim?, exhibiting memory cell phenotype. Functionally, CD39 expression on memory and Treg cells confers protection against ATP-induced apoptosis. Compared with Foxp3?CD39?naïve T cells, Foxp3?CD39cells freshly isolated from non-immunized mice express at rest significantly higher levels of mRNA for T-helper lineage-specific cytokines IFN-? (Th1), IL-4IL-10 (Th2), IL-17AF (Th17), as well as pro-inflammatory cytokines, and rapidly secrete these cytokines upon stimulation. Moreover, the presence of Foxp3?CD39cells inhibits TGF-? induction of Foxp3 in Foxp3?CD39?cells. Furthermore, when transferred in vivo, Foxp3?CD39cells rejected MHC-mismatched skin allografts in a much faster tempo than Foxp3?CD39?cells. Thus, besides Tregs, CD39 is also expressed on pre-existing memory T cells of Th1-, Th2- and Th17-types with heightened alloreactivity.

The outcome of T-cell-mediated responses, immunity or tolerance, critically depends on the balance of cytopathic versus regulatory T (Treg) cells. In the creation of stable tolerance to MHC incompatible allografts, reducing the unusually large mass of donor-reactive cytopathic T effector (Teff) cells via apoptosis is often required. Cyclosporine (CsA) blocks activation-induced cell death (AICD) of Teffcells, and is detrimental to tolerance induction by costimulation blockade, whereas Rapamycin (RPM) preserves AICD, and augments the potential of costimulation blockade to create tolerance. While differences between CsA and RPM in influencing apoptosis of activated graft-destructive Teffcells are apparent, their effects on graft-protective Tregcells remain enigmatic. Moreover, it is unclear whether tolerizing regimens foster conversion of naïve peripheral T cells into alloantigen-specific Tregcells for graft protection. Here we show, using reporter mice for Tregmarker Foxp3, that RPM promotes de novoconversion of alloantigen-specific Tregcells, whereas CsA completely inhibits this process. Upon transfer, in vivoconverted Tregcells potently suppress the rejection of donor but not third party skin grafts. Thus, the differential effects of RPM and CsA on Teffand Tregcells favor the use of RPM in shifting the balance of aggressive to protective type alloimmunity.