RESUMO
Resident memory T cells (TRMs), which are memory T cells that are retained locally within tissues, have recently been described as antigen-specific frontline defenders against pathogens in barrier and nonbarrier epithelial tissues. They have also been noted for perpetuating chronic inflammation. The conditions responsible for TRM differentiation are still poorly understood, and their contributions, if any, to sterile models of chronic kidney disease (CKD) remain a mystery. In this study, we subjected male C57BL/6J mice and OT-1 transgenic mice to five consecutive days of 2 mg/kg aristolochic acid (AA) injections intraperitoneally to induce CKD or saline injections as a control. We evaluated their kidney immune profiles at 2 wk, 6 wk, and 6 mo after treatment. We identified a substantial population of TRMs in the kidneys of mice with AA-induced CKD. Flow cytometry of injured kidneys showed T cells bearing TRM surface markers and single-cell (sc) RNA sequencing revealed these cells as expressing well-known TRM transcription factors and receptors responsible for TRM differentiation and maintenance. Although kidney TRMs expressed Cd44, a marker of antigen experience and T cell activation, their derivation was independent of cognate antigen-T cell receptor interactions, as the kidneys of transgenic OT-1 mice still harbored considerable proportions of TRMs after injury. Our results suggest a nonantigen-specific or antigen-independent mechanism capable of generating TRMs in the kidney and highlight the need to better understand TRMs and their involvement in CKD.NEW & NOTEWORTHY Resident memory T cells (TRMs) differentiate and are retained within the kidneys of mice with aristolochic acid (AA)-induced chronic kidney disease (CKD). Here, we characterized this kidney TRM population and demonstrated TRM derivation in the kidneys of OT-1 transgenic mice with AA-induced CKD. A better understanding of TRMs and the processes by which they can differentiate independent of antigen may help our understanding of the interactions between the immune system and kidneys.
Assuntos
Ácidos Aristolóquicos , Diferenciação Celular , Rim , Células T de Memória , Camundongos Endogâmicos C57BL , Insuficiência Renal Crônica , Animais , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/metabolismo , Masculino , Ácidos Aristolóquicos/toxicidade , Rim/imunologia , Rim/metabolismo , Rim/patologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , Camundongos Transgênicos , Memória Imunológica , Modelos Animais de Doenças , CamundongosRESUMO
Building a competitive research program within a department of surgery requires a significant commitment by the department and the institution to provide the necessary resources for faculty recruitment, retention of current faculty, and physical space/infrastructure to support research activities. We expanded the academic footprint of our department as demonstrated by the expansion of the department of surgery research funding by 13-fold over a period of 7 years, resulting in an increase in national ranking from 55th place to 10th place in the National Institutes of Health extramural funding. This required attention to multiple factors that affect the ability of faculty to establish and maintain competitive research programs. We executed a plan that established a leadership structure that coordinates resources and provides mentorship to faculty. The department invested heavily in the recruitment of new faculty, especially junior faculty, but also some mid-career and senior investigators to develop a critical mass in specific areas for competitive large grant and program project applications. The pipeline of new trainees interested in research was augmented by successful training grant applications that created a mechanism by which residents and fellows can pursue research for periods ranging from a few weeks to 2 years. Administrative infrastructure was created to assist faculty in grant submissions as well as post-award management. Finally, in partnership with institutional leadership, the department acquired the physical space necessary to support both dry-lab and wet-lab research activities. To achieve true excellence, an academic surgery department must maintain excellence in both the clinical and research areas, which, in the context of an academic medical center, are not separate goals.
Assuntos
Pesquisa Biomédica , Mentores , Estados Unidos , Humanos , Docentes , National Institutes of Health (U.S.) , Centros Médicos Acadêmicos , LiderançaRESUMO
Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced endometrial NK cells and altered pregnancy phenotypes. We further show that the NK reduction in UTx is due to impaired transcriptional programming of NK tissue residency due to blockade of the transcription factor nuclear factor of activated T cells (NFAT). NFAT-dependent genes played a role in multiple molecular circuits governing tissue residency in uNKs, including early residency programs involving AP-1 transcription factors as well as TGFß-mediated upregulation of surface integrins. Collectively, our data identify a previously undescribed role for NFAT in uterine NK tissue residency and provide novel mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue resident NK subsets in humans. One Sentence Summary: Role of NFAT in uterine NK cell tissue residency.
RESUMO
Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.