Foxp3+ T-regulatory cells (Tregs) normally serve to attenuate immune responses and are key to maintenance of immune homeostasis. Over the past decade, Treg cells have become a major focus of research for many groups, and various functional subsets have been characterized. Recently, the Ikaros family member, Helios, was reported as a marker to discriminate naturally occurring, thymic-derived Tregs from those peripherally induced from naïve CD4+ T cells. We investigated Helios expression in murine and human T cells under resting or activating conditions, using well-characterized molecules of naïve/effector/memory phenotypes, as well as a set of Treg-associated markers. We found that Helios-negative T cells are enriched for naïve T cell phenotypes and vice versa. Moreover, Helios can be induced during T cell activation and proliferation, but regresses in the same cells under resting conditions. We demonstrated comparable findings using human and murine CD4+Foxp3+ Tregs, as well as in CD4+ and CD8+ T cells. Since Helios expression is associated with T cell activation and cellular division, regardless of the cell subset involved, it does not appear suitable as a marker to distinguish natural and induced Treg cells.

Death rates from drug overdoses have nearly doubled since 2003, with over 47 000 deaths in 2014. This is largely attributable to the opioid epidemic. If the unfortunate deaths of otherwise healthy people have yielded an increase in organ donors, then this might serve as perhaps the only comforting factor among this tragic and unnecessary loss of life. In this viewpoint, we present data from the Organ Procurement and Transplantation Network (OPTN) that show how the greatest relative increases in the mechanism of death among deceased donors from 2003 to 2014 were drug overdoses. Unfortunately, despite the absolute increase in the number of donors who died from a drug overdose, the mean organ yield was significantly lower than in other categories, in part due to concerns about disease transmission. In this paper, we present data on the changes in donation from donors with a drug overdose as a result of the opioid epidemic and discuss the need to educate transplant candidates and their physicians about the low risk of disease transmission compared to the greater risk of dying on a transplant waitlist.

Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α–KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.

Kidney transplantation is a cost-saving treatment that extends the lives of patients with ESRD. Unfortunately, the kidney transplant waiting list has ballooned to over 100,000 Americans. Across large areas of the United States, many kidney transplant candidates spend over 5 years waiting and often die before undergoing transplantation. However, more than 2500 kidneys (>17% of the total recovered from deceased donors) were discarded in 2013, despite evidence that many of these kidneys would provide a survival benefit to wait-listed patients. Transplant leaders have focused attention on transplant center report cards as a likely cause for this discard problem, although that focus is too narrow. In this review, we examine the risks associated with accepting various categories of donated kidneys, including discarded kidneys, compared with the risk of remaining on dialysis. With the goal of improving access to kidney transplant, we describe feasible proposals to increase acceptance of currently discarded organs.

Seventy percent of peripheral immature conventional (B2) B cells fail to develop into mature B cells. The nature of this cell loss has not been characterized; the process that governs which immature B cells develop into long-lived peripheral B cells could be either stochastic or selective. Here, we demonstrate that this step is in fact selective, in that the fate of an immature B cell is highly dependent on its Ig receptor specificity. A significant skewing of the B cell receptor repertoire occurs by the time cells enter the mature B cell fraction, which indicates that there is selection of only a minority of immature B cells to become mature B cells. Because only a few heavy-light chain pairs are enhanced of the diverse available repertoire, we favor the idea that selection is positive for these few heavy-light chain pairs rather than negative against nearly all others. Because most immature B cells are lost at this transition, this putative positive selection event is likely to be a major force shaping the mature B cell receptor repertoire available for adaptive immune responses.

In a cross‐sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T‐regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg‐specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty‐eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =−0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =−0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long‐term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.