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Approximately 6% of deceased kidney donors (DKDs) are diabetic; their kidneys may be associated with worse allograft survival, but published studies suggest that recipient diabetes status has a greater impact on mortality and survival. Since biopsy findings are the most common reason for organ discard, we sought to understand histologic and clinical factors that influence graft survival in patients who receive a kidney from a diabetic DKD. We retrospectively reviewed our institutional experience from 2005 to 2019, and re-evaluated pre-implantation and earliest post-transplant biopsies. Histologic findings were compared against a control cohort of non-diabetic DKD. Of 829 adult DKD transplants, 37 (4.5%) came from diabetic donors. There was no significant difference in diabetic vs. non-diabetic DKD graft survival for all-comers; however, when stratified by duration of donor diabetes, donor diabetes ≥6 years was associated with graft failure. In 25 patients with post-transplant biopsies available, diabetic DKD allografts had significantly greater non-glomerular chronic injury than non-diabetic DKD allografts. Moderate arteriolar hyalinosis (in 24%), moderate tubular atrophy and interstitial fibrosis (IFTA, in 36%), and diabetic glomerulopathy (in 24%) on early post-transplant biopsy were associated with allograft failure. Pre-implantation frozen section discrepancies were more common in long-standing donor diabetes, and arteriolar hyalinosis and IFTA scores on frozen accurately prognosticated graft loss. There was no morphologic improvement in lesions of diabetic nephropathy on short-term follow-up. In conclusion, donor diabetes ≥6 years, and histologic findings on frozen section and early post-transplant biopsy are associated with diabetic DKD allograft loss.

In 2017 United Network for Organ Sharing (UNOS) implemented a simultaneous liver kidney transplant (SLK) allocation policy. Our institution uses a more restrictive criteria for SLK; thus, we have a group of patients that would have qualified for SLK under the new allocation policy but received liver transplantation alone (LTA). We compared survival and post-operative renal function in patients that received LTA stratified by whether they met the new UNOS SLK criteria. There was no difference in graft and patient survival. The majority (95%) of LTA patients meeting the UNOS SLK criteria did not need dialysis at one year, with a mean eGFR increase from 23mL/min preoperatively to 48mL/min at one year. Of those with eGFR ≤ 20mL/min at one month after surgery, the majority did regain adequate renal function. The implementation of the UNOS SLK allocation policy was appropriate in the previously unregulated area. This policy provides an excellent framework for those that may benefit from SLK. Our data suggests that a more restrictive policy may be possible in order to promote the best use of donated organs. The current safety net is appropriately positioned to capture patients in need of subsequent kidney transplant.

Morbidity and mortality due to viral infections are major health concerns, particularly when individuals are vitamin A (VitA) deficient (VAD). Previous literature has suggested that CD11c+ dendritic cells in the gastrointestinal tract are largely responsible for VitA metabolism and the associated homing and function of gut lymphocytes. To determine if/how VitA impacts virus-specific immunity in the upper respiratory tract (RT), we administered virus intranasally (IN) to VAD mice. We found that virus-specific B- and T-cell responses were altered, with a significant down-regulation of IgA in the nasal wash of VAD mice compared to controls. We next asked if RT cells could autonomously support VitA-driven IgA production. We harvested CD11c+ and Cd11c- cells from diffuse nasal associated lymphoid tissues and found that both expressed RALDH mRNA, as required for VitA metabolism. Furthermore, preliminary data showed that both populations enhanced IgA in activated splenocyte cultures. To investigate which CD11c- cells were pertinent to function, we tested a RT epithelial cell line. These cells: (i) expressed RALDH mRNA and (ii) enhanced IgA in the presence of VitA A derivatives. In total, data highlighted the autonomous potential of RT cells to support a VitA-driven immune response. Results may ultimately instruct a clinical healthcare initiative to supplement VAD individuals with VitA by the oral or IN route, to enhance RT immunity toward viral infections and viral vaccines.

Memory T cells resident in peripheral tissues are key to establishing protective immunity to pathgens. There exist seemingly paradoxical concepts in the understanding of mechanisms regulating tissue-specific migration of CD8 memory T cells. One concept is that tissue-specific homing is imprinted by exposure to environmental factors during T cell priming. A contrasting concept is that memory T cells acquire tissue-specific homing properties through continued maturation in the periphery. Our mouse models of respiratory virus infection demonstrate that continued recruitment of CD8 T cells to the airways during steady-state memory is mediated by sequential events. Initial priming of CD8 T cells in the lung draining lymph node imprints memory CD8 T cells with the capacity to access residual antigen depots. Stimulation by residual antigen in the weeks to months following resolution of infection then promotes continued maturation and airway migration of CD8 T cells during steady-state memory. Interestingly, despite the formation of residual antigen depots following intraperitoneal, subcutaneous, or intramuscular infection, the resulting memory T cells ignore this maturation stimulus and fail to migrate to the airways despite exposure to lung inflammation. We hypothesize the site of priming is critical for imprinting memory T cells with the ability to access the additional signals required for continued maturation and effective migration of memory T cells to peripheral tissues.

Cytokines are soluble signaling molecules that orchestrate immune responses, regulating both immune protection and immunopathology. T cell differentiation is characterized by distinctive changes in cytokine production, but less is known about concomitant changes in cytokine responsiveness. Here we report that CD8+ T cell differentiation imposes permanent alterations in the cytokine receptor repertoire. We show that influenza virus-specific CD8+ memory T cells in both humans and mice lose responsiveness to interleukin (IL)-27. This loss is due to persistent downregulation of the shared gp130 cytokine receptor chain on effector and memory T cells and occurs as a direct consequence of antigenic stimulation. Loss of IL-27 responsiveness renders CD8+ memory T cells deficient in their expression of the immunosuppressive cytokine IL-10 during recall responses. Together our data reveal a previously unappreciated feature of CD8+ T cell differentiation, in which the selective and persistent loss of specific cytokine receptors defines the functional potential of memory cells during rechallenge. The altered cytokine responsiveness of effector and memory T cells has fundamental implications for the functional manipulation of these cells in vivo.

Respiratory virus infections are a major health problem in the elderly. This is due to declining immune responsiveness in the elderly and the development of CD8+ T cell clonal expansions (TCE) that perturb the memory T cell pool. We recently showed that TCE can arise over time from memory CD8+ T cells established by an acute respiratory viral infection. Virus-specific TCE are phenotypically identical to conventional memory cells and do not express the characteristics of exhausted cells. Since TCE can dominate the memory T cell pool, it is essential to determine the rate at which they develop, and their ability to mount a recall response to secondary pathogen challenge in vivo. In the current study, we developed an assay to detect developing TCE in a cohort of mice following Sendai virus infection and found a progressive increase in the appearance of TCE within the first year following infection. Using a dual adoptive transfer approach to address the recall potential of virus-specific TCE, we demonstrate that the majority of TCE examined are poorly responsive to a secondary infection. Taken together, the data suggest that the development of TCE is a common occurrence due to the progressive dysregulation of the virus-specific memory T cell pool with age, and many TCE are profoundly defective in their ability to mediate recall responses.

Antiviral CD8 T cells are essential for protection during murine gammaheresvirus-68 (γHV68) infection. We recently identified a large panel of epitope-specific CD8 T cell responses that were differentially regulated by antigen presentation during the establishment of viral latency, but how these T cell responses are maintained throughout latent infection is unclear. Here we show that recent thymic emigrants are primed during latency, accumulate over time, and can proliferate in response to experimentally-induced viral reactivation. We found that in contrast to ORF6487- and ORF61524-specific responses, CD8 T cells specific for the ORF75c940 epitope primed during latency were deficient in their ability to respond during reactivation. This defect was not a result of impaired generation of ORF75c940-specific cells during latency or a lack of antigen presentation during reactivation, but rather appears to be a consequence of reduced proliferation following stimulation. The finding of epitope-specific differences in proliferative capacity suggests that the functionality of latency-primed responses may be regulated by differential antigen presentation or viral gene expression during latency. These findings have important implications for the development of therapeutic vaccine strategies against latent gammaherpesvirus infections.

The development of T cell memory from naïve precursors is a complex process influenced by molecular cues received during T cell activation and differentiation. In the present study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8 T cell contraction and memory generation following influenza virus infection. Using mixed bone marrow chimeras, we find that Ccr5-/- Cxcr3-/- cells show markedly decreased contraction following viral clearance, leading to the establishment of massive numbers of memory CD8 T cells. Ccr5-/- Cxcr3-/- cells show preferential localization to the non-inflamed interstitial spaces of the infected lung, which coincides with reduced expression of the activation marker CD69 and the rapid appearance of CD127hi KLRG1lo memory precursor cells after viral clearance. Importantly, influenza-specific effector Ccr5-/- Cxcr3-/- CD8 T cells in the lung could be activated in vivo by the addition of exogenous antigen, which restored effector T cell contraction and significantly reduced memory T cell generation following viral clearance. Together, the data support a model of memory CD8 T cell generation where the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8 T cell activation and differentiation, which ultimately regulates effector versus memory cell-fate decisions.