Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.

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Adoptive transfer (AT) of T cells forced to express tumor-reactive T-cell receptor (TCR)genes IntroductionHematopoietic stem cell transplantation (HCT) from human leukocyte antigen-mismatched family donors is a potentially curative option for patients with high-risk hematologic malignancies lacking a human leukocyte antigen-matched donor. 1,2 For haploidentical HCT, this procedure typically requires rigorous T-cell depletion of the graft eliminating the cellular component, which can contribute to the curative potential of an allogeneic HCT. 3 To overcome this limitation, donor-derived lymphocytes have been infused later after transplantation to provide a graft-versus-malignancy effect. Although preclinical and clinical studies were initiated to minimize the side effects of such a procedure, 4,5 the risk of inducing severe graft-versus-host disease (GVHD) remains substantial, and relapse rates continue to be significant in part because of tumor escape mechanisms that evolve over time. 6 Enforced expression of T-cell receptor (TCR) genes directed against a tumor-associated antigen (TAA) has been explored as a means by which the potency of T-cell adoptive transfer (AT) may be augmented. When using allogeneic T cells, such an approach may serve to direct the donor T-cell response preferentially to the host leukemia cells instead of the normal host cells, thereby increasing the therapeutic index of T cell AT. Lessons from studies of murine autologous T-cell AT models have shown that: (1) TCR gene therapy can be expected to break tolerance against selfantigens, such as tumor-associated antigens; (2) with few exceptions, TCR gene transfer was associated with an acceptable toxicity profile; and (3) the transfer of TCR-engineered T cells has been shown to impact large tumor burdens. 7 However, clinical translation of TCR gene-modified T-cell AT has been hampered by the growing evidence that in vivo proliferation and persistence of engineered T cells are more limited than needed for an optimal antitumor response. 8,9 Increasingly, T-cell AT is performed in the context of a lymphodepleted recipient to provide a more favorable environment for their homeostatic expansion. 10 However, whereas cytokines that accumulate in lymphodepleted recipients can drive T-cell expansion until the cytokines are consumed, 11 long-term T-cell activation and expansion require continued TCR engagement. In this study, we sought to take advantage of dual-specific TCR-transduced T cells obtained from major histocompatibility complex (MHC)-mismatched donors that would receive allogeneic MHC antigenic signals via the endogenous TCR that may be useful in sustaining the persistence of adoptively transferred T cells. In support of this hypothesis, virus-specific T cells reprogrammed to express a TCR-directed against host hematopoietically restricted minor histocompatibility antigens remained responsive against their allo-targets without losing their viral reactivity. 12 Here, we evaluated the converse concept that the in vivo infusion of T cells forced...

Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3+ Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3+ Tregs for therapeutic use in transplantation medicine.

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High‐fat high‐carbohydrate (HF‐HC) diet feeding of NASH‐resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)‐deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF‐HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen‐driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1−/− mice was substantially worsened and accompanied by a sharp increase of M1‐like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti‐cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.