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Our understanding of tissue-resident memory T (TRM) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about TRM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie TRM maintenance in a kidney transplantation model in which TRM cells drive rejection. In contrast to acute infection, we found that TRM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after TRM cells were established was sufficient to disrupt TRM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during TRM maintenance led to a decline in TRM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 TRM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity. Long-term maintenance: Successful kidney transplantation relies on prevention of chronic rejection, but details of mechanisms maintaining this response are not fully understood. Tieu et al. characterize a role for CD8+ tissue-resident memory T (TRM) cells in mediating chronic rejection. They observed that the maintenance of TRM cells in kidney allografts required the presence of cognate antigen, antigen presentation, or antigen sensing. Depletion of dendritic cells (DCs) within the graft or blockade of antigen presentation prevented TRM maintenance and decreased pathological responses in kidney allografts. In addition, expression of the IL-15 receptor on TRM or IL-15 transpresentation also supported TRM maintenance, and IL-15 receptor blockade was sufficient to prevent chronic allograft rejection. Together, these findings demonstrate that DC presentation of antigen and IL-15 each contribute to TRM maintenance in a chronic allograft rejection model. —CNF [ABSTRACT FROM AUTHOR]

Memories of rejection: Long-term graft survival after organ transplantation can be hindered by immune-mediated allograft rejection; thus, understanding these immune responses is crucial to developing new transplant-supporting therapies. Tissue-resident memory T cells (TRM), a subset of memory T cells that reside in barrier tissues and do not recirculate, are detectable in transplanted organs, but it is unclear if they contribute to allograft rejection. Abou-Daya et al. created a mouse model of T cell–mediated kidney transplant rejection, showing that adoptively transferred, kidney antigen–specific effector T cells differentiated into functional, nonrecirculating antigen-specific TRM in the transplanted kidneys. These kidney antigen–specific TRM induced allograft rejection. These data suggest that TRM in transplanted allografts can contribute to rejection and that targeting alloreactive TRM might improve long-term graft survival in transplant recipients. Tissue-resident memory T cells (TRM) contained at sites of previous infection provide local protection against reinfection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long term in allografts, but it is not known whether they are exhausted or are functional memory T cells. Using a mouse model of kidney transplantation, we showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subsequently caused allograft rejection. TRM identity was established by surface phenotype, transcriptional profile, and inability to recirculate in parabiosis and retransplantation experiments. Graft TRM proliferated locally, produced interferon-γ upon restimulation, and their in vivo depletion attenuated rejection. The vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single-cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue-resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics. [ABSTRACT FROM PUBLISHER]