Diverse T cell types accumulate at the human maternal fetal interface (MFI) during pregnancy to orchestrate immune tolerance for foreign fetal/placental tissues and immunity to pathogens. Yet, the dynamics of T cell influx and function at the MFI remain poorly defined. Conventional specific pathogen free (SPF) murine models fail to replicate the number and diversity of T cells in the human MFI, hindering mechanistic study of MFI T cells. Here we present an innovative use of a natural microbial exposure (NME) mouse model that enhances T cell influx and diversity in the MFI. We defined changes in the MFI of NME mice, relative to SPF mice and human tissues using transcriptomic and proteomic approaches. Physiological maternal microbial burden reproduced key features of human MFI immunology by i) significantly increasing the numbers and diversity of CD4 and CD8 effector and memory T cells at the MFI; ii) skewing the CD8 T cell composition towards tissue resident memory phenotypes with increased signatures of activation and dysfunction similar to human decidual T cells; and iii) expanding unconventional γδ T cells and Killer Lectin-like Receptors (KLR) expressing T cell types at the MFI, representative of an enhanced ability to interact with placental trophoblasts or infected cells. Thus, maternal microbial exposure induces vast changes to T cell numbers, diversity and functions at the MFI that models human MFI T cells with great fidelity. The NME model allows for improved translational investigation of the mechanisms of T cell tolerance, immunity, and inflammation in pregnancy.
Copyright © 2025 Whillock, Smith, Burger, Sridhar, Lindgren, Berg, Tsuda, Mahajan, Tilburgs and Schuldt.

The incomplete understanding of epididymal mucosal immunity is a significant contributing factor to the classification of many male infertility cases as idiopathic. Conditions that disrupt the immune balance in the male reproductive tract, such as vasectomy and infections, can expose sperm to the immune system, leading to increased production of anti-sperm antibodies (ASAs) and subsequent reproductive challenges. Regulatory T cells (Tregs) regulate inflammation and maintain sperm tolerance. In a murine model, we demonstrated that disrupting sperm immunotolerance induces chronic autoimmune responses characterized by antibody production targeting sperm and reproductive tissue autoantigens and unique tissue-specific immune cell signatures in the epididymis and testis. Such inflammatory features impair sperm function, contribute to epididymal damage, and drive sustained male subfertility. Tertiary lymphoid structures (TLSs) were formed within the epididymis after Treg depletion, defined by clusters of heterogenous B and T cells, fibroblasts, and endothelial cells. These ectopic structures perpetuate inflammation and lower the activation threshold for future immune threats. Similar isotypes of autoantibodies were detected in the seminal plasma of infertile patients, suggesting shared mechanistic pathways between mice and humans. Overall, we provide an in-depth understanding of the diverse B- and T-cell dynamics and TLS formation during epididymitis to develop precision-targeted therapies for infertility and chronic inflammation. Additionally, this immunological characterization of the epididymal microenvironment has the potential to identify novel targets for the development of male contraceptives. One Sentence Summary Understanding the epididymal immune cell landscape dynamics aids in developing targeted therapies for infertility and contraception.

Plexiform neurofibromas (PNFs) are benign nerve tumors driven by loss of the NF1 tumor suppressor in Schwann cells. PNFs are rich in immune cells, but whether immune cells are necessary for tumorigenesis is unknown. We show that inhibition of stimulator of interferon gene (STING) reduces plasma CXCL10, tumor T cell and dendritic cell (DC) recruitment, and tumor formation. Further, mice lacking XCR-1+ DCs showed reduced tumor-infiltrating T cells and PNF tumors. Antigen-presenting cells from tumor-bearing mice promoted CD8+ T cell proliferation in vitro, and PNF T cells expressed high levels of CCL5, implicating T cell activation. Notably, tumors and nerve-associated macrophages were absent in Rag1-/-; Nf1f/f; DhhCre mice and adoptive transfer of CD8+ T cells from tumor-bearing mice restored PNF initiation. In this setting, PNF shrunk upon subsequent T cell removal. Thus, STING pathway activation contributes to CD8+ T cell-dependent inflammatory responses required for PNF initiation and maintenance.

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.
© 2024. The Author(s).

ABSTRACT Interleukin-18 is an acute phase pro-inflammatory molecule crucial for mediating viral clearance by activating Th1 CD4 + , cytotoxic CD8 + T, and NK cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18 stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures restoration of immune competence after acute insults like stress, infection, chemotherapy, and radiation. NK cells suppressed thymus recovery by aberrantly targeting thymic epithelial cells (TECs), which act as the master regulators of organ function and regeneration. Together these studies reveal a novel pathway regulating tissue regeneration in the thymus and offer IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy for its capacity to elicit a type-1 immune response, these findings also offer insight into potential off-target effects.