IntroductionOrthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. Ischemia/reperfusion injury (IRI) occurs as an inevitable consequence of the transplant process, beginning with organ procurement and preservation and followed by reperfusion of the donor organ with recipient blood during transplant (1). Data from murine models have indicated that liver IRI has hypoxic cellular stress and inflammation-mediated injury components (2-5). Local circulatory damage first induces endogenous reactive oxygen species production causing hepatocyte death. This cellular damage initiates the second phase by recruiting and activating innate immune cells at the site of injury. IRI is then further exacerbated by the adaptive immune system; indeed, activated CD4 + T cells are essential in promoting IRI-related inflammation and hepatocyte damage in mice. IRI can lead to primary graft nonfunction and need for retransplantation (6) and predisposes the recipient to both acute and chronic rejection and graft loss as well as decreases the pool of transplantable organs. Although IRI is a signifi-BACKGROUND. Orthotopic liver transplant (OLT) is the primary therapy for end-stage liver disease and acute liver failure. However, ischemia/reperfusion injury (IRI) can severely compromise allograft survival. To understand the evolution of immune responses underlying OLT-IRI, we evaluated longitudinal cytokine expression profiles from adult OLT recipients before transplant through 1 month after transplant.

Type 1 regulatory T cells suppress alloreactive immune cells after adoptive transfer in a CTLA-4 and PD-1–mediated manner.

Microbial metabolites are an emerging class of mediators influencing CD4+ T cell function. To advance the understanding of direct causal microbial factors contributing to Crohn’s disease, we screened 139 predicted Crohn’s disease-associated microbial metabolites for their bioactivity on human CD4+ T cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T cell bioactivity, 3 previously reported and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNγ-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T cell bioactivity among Crohn’s disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T cell energy metabolism.

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Background BK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control. Methods Peripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T cell activation, exhaustion, and maturation. Results BK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a. Conclusions Noninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia. 5