Late-onset sepsis (LOS) and other systemic bloodstream infections are notable causes of neonatal mortality, particularly in prematurely born very low birth weight infants. Breastfeeding in early life has numerous health benefits, impacting the health of the newborn in both the short-term and in the long-term. Though the known benefits of an exclusive mother’s own milk diet in early life have been well recognized and described, it is less understood how breastfed infants enjoy a potential reduction in risk of LOS and other systemic infections. Here we review how gut residing pathogens within the intestinal microbiota of infants can cause a subset of sepsis cases and the components of breastmilk that may prevent the dissemination of pathogens from the intestine.

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The shifting paradigm regarding immune surveillance of the central nervous system (CNS) has shed light on immune cell networks thought to be absent from healthy brain tissue. Resident memory T cells (TRM) are a unique subset of memory T cells that persist within non-lymphoid tissues to provide rapid onset protection against reinfection. Recently, brain TRM (bTRM) have been identified in humans, with CNS or peripheral infection, or vaccination leading to bTRM establishment in mice. While bTRM are important for protection of the CNS against reinfection, their regulation and involvement in shaping the neuroimmune landscape remains unknown. Here, we take a reductionist approach employing viral-derived peptides to show that CD8+ bTRM reactivation is sufficient to initiate a cascade of innate and adaptive immune activation in the brain. Specifically, bTRM reactivation triggered activation of NK cells, T cells, microglia, and induced dendritic cell (DC) maturation, including upregulation of lymph node homing molecules. Reactivated bTRM also promoted accumulation of DCs in draining lymph nodes, and macrophages, monocyte-derived DCs, T cells and NK cells in the brain. Our preliminary data suggests that PD-1:PD-L1 signaling regulates the magnitude of this response, as PD-L1 blockade led to enhanced bTRM activation and neuroinflammation. We anticipate our results to illuminate roles for PD-1 signaling on bTRM in the context of pathogen clearance, and neurologic toxicities seen in cancer patients following PD-1 inhibitor treatment. This study will also provide insight into the pathologic or protective capacity of bTRM in neurologic diseases where T cells are implicated, such as Alzheimer’s disease, multiple sclerosis, and brain cancer. Supported by grants from NIH (K22 AI148508-02, T32 AI007363)

Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host, including the brain, and are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate the mouse and human glioblastoma microenvironment. Reactivating virus-specific memory T cells through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific memory T cells are a significant part of the glioblastoma immune microenvironment and may be leveraged to promote anti-tumoral immunity. Supported by UMN SPORE Program Project Planning grant (DM, CCC), NCI 1R01CA238439 (DM), Humor to Fight the Tumor Foundation (JN), NCI 5P30CA023108-42 (PR)