The transcription factor T cell factor-1 (TCF-1) is encoded by Tcf7 and plays a significant role in regulating immune responses to cancer and pathogens. TCF-1 plays a central role in CD4 T cell development; however, the biological function of TCF-1 on mature peripheral CD4 T cell-mediated alloimmunity is currently unknown. This report reveals that TCF-1 is critical for mature CD4 T cell stemness and their persistence functions. Our data show that mature CD4 T cells from TCF-1 cKO mice did not cause graft versus host disease (GvHD) during allogeneic CD4 T cell transplantation, and donor CD4 T cells did not cause GvHD damage to target organs. For the first time, we showed that TCF-1 regulates CD4 T cell stemness by regulating CD28 expression, which is required for CD4 stemness. Our data showed that TCF-1 regulates CD4 effector and central memory formation. For the first time, we provide evidence that TCF-1 differentially regulates key chemokine and cytokine receptors critical for CD4 T cell migration and inflammation during alloimmunity. Our transcriptomic data uncovered that TCF-1 regulates critical pathways during normal state and alloimmunity. Knowledge acquired from these discoveries will enable us to develop a target-specific approach for treating CD4 T cell-mediated diseases.

Background: Immune-related adverse events are a management challenge in patients receiving immune checkpoint inhibitors (ICIs). The most common renal immune-related adverse event, acute interstitial nephritis (AIN), is associated with patient morbidity and mortality. AIN, characterized by infiltration of renal tissue with immune cells, may be analogous to kidney transplant rejection. We evaluated clinical variables and pathologic findings to identify predictors of renal response and overall survival (OS) in patients with ICI-induced AIN. Design, setting, participants, and measurements: We reviewed the records and biopsy specimens of all 35 patients treated for ICI-induced AIN at our institution, between August 2007 and August 2020, who had biopsy specimens available. Two board-certified renal pathologists graded the severity of inflammation and chronicity using transplant rejection Banff criteria and performed immunohistochemistry analysis. Patients were categorized as renal responders if creatinine had any improvement or returned to baseline within 3 months of initiating treatment for AIN. Clinical and pathologic characteristics and OS were compared between responders and non-responders. Results: Patients with high levels of interstitial fibrosis were less likely to be responders than those with less fibrosis (p = 0.02). Inflammation, tubulitis, the number of eosinophils and neutrophils, and the clustering or presence of CD8+, CD4+, CD20+, or CD68+ cells were not associated with renal response. Responders had better OS than non-responders (12-month OS rate 77% compared with 27%, p = 0.025). Responders who received concurrent ICIs had the best OS, and non-responders who did not receive concurrent ICIs had the worst OS (12-month OS rate 100% for renal response and concurrent ICIs, 72% for renal response and no concurrent ICIs, and 27% for no renal response and no concurrent ICIs; p = 0.041). Conclusions: This is the first analysis of ICI induced nephritis where a detailed pathological and clinical evaluation was performed to predict renal response. Low levels of interstitial fibrosis in kidney tissue are associated with renal response to treatment for ICI-induced AIN, and the renal response and use of concurrent ICIs are associated with better OS in these patients. Our findings highlight the importance of the early diagnosis and treatment of ICI-AIN, while continuing concurrent ICI therapy.

Plasmacytoid and micropapillary variants of high-grade urothelial carcinoma (HGUC) exhibit unique histologic morphology and very aggressive clinical behavior. However, the morphology of these 2 variants in urinary cytology is not well studied and evaluated using The Paris System for reporting urinary cytology. A database search was performed in all patients with the diagnosis of plasmacytoid or micropapillary HGUC. A total of 5 patients with positive urinary cytology cases were identified. The cytomorphology of every urinary cytology case was correlated with the histologic features in the surgical specimens from the same patient. One urine and 4 bladder washings were evaluated. Cytologically, plasmacytoid HGUCs are characterized by single, large tumor cells with hyperchromasia, irregular nuclear membranes, and vacuolated cytoplasm. The nuclear-to-cytoplasmic (N:C) ratio was less than 0.5 in many of the malignant cells due to the abundant cytoplasm. The cytology features of micropapillary HGUC include the presence of micropapillae of tumor cells with no fibrovascular core. Individual high-grade urothelial cells were also identified in all 4 cases, but 1 (25%) of these had only rare cells meeting The Paris System criteria for HGUC due to abundant cytoplasm and lack of hyperchromasia in most malignant cells. Plasmacytoid and micropapillary variants of HGUC have unique cytomorphologic features in urinary cytology specimens, which are reflective of the corresponding histological findings. These 2 clinically aggressive variants of HGUC may not be as readily interpreted as malignant using The Paris System for reporting urinary cytology, creating potential diagnostic pitfalls.

Histology diagnosis is essential for the monitoring and management of kidney transplant patients. Nowadays, the accuracy and reproducibility of histology have been criticized when compared with molecular microscopy diagnostic system (MMDx). Our cohort included 95 renal allograft biopsies with both histology and molecular diagnoses. Discrepancies between histology and molecular diagnosis were assessed for each biopsy. Among the 95 kidney allograft biopsies, a total of 6 cases (6%) showed clear (n = 4) or borderline (n = 2) discrepancies between histology and molecular diagnoses. Four out of the six (67%) were cases with pathologically and clinically confirmed active infections that were diagnosed as mild to moderate T-cell-mediated rejection (TCMR) with MMDx. Two cases showed pathological changes that were not sufficient to make a definitive diagnosis of active rejection via histology, while MMDx results showed antibody-mediated rejection (ABMR). In addition, there were six cases with recurrent or de novo glomerular diseases diagnosed only via histology. All other biopsy results were in an agreement. Our results indicate that histology diagnosis of kidney allograft biopsy is superior to molecular diagnosis in the setting of infections and glomerular diseases; however, MMDx can provide helpful information to confirm the diagnosis of active ABMR.