SUMMARYThe Enterobacteriaceae are Gram-negative bacteria and include commensal organisms as well as primary and opportunistic pathogens that are among the leading causes of morbidity and mortality worldwide. Although Enterobacteriaceae often comprise less than 1% of a healthy intestine’s microbiota1, some of these organisms can bloom in the inflamed gut2–5; indeed, expansion of enterobacteria is a hallmark of microbial imbalance known as “dysbiosis”6. Microcins are small secreted proteins that possess antimicrobial activity in vitro7,8, but whose role in vivo has been unclear. Here we demonstrate that microcins enable the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to limit expansion of competing Enterobacteriaceae (including pathogens and pathobionts) during intestinal inflammation. Microcin-producing EcN limited growth of competitors in the inflamed intestine, including commensal E. coli, adherent-invasive E. coli, and the related pathogen Salmonella enterica. Moreover, only therapeutic administration of the wild-type, microcin-producing EcN to mice previously infected with S. enterica substantially reduced intestinal colonization of the pathogen. Our work provides the first evidence that microcins mediate inter and intra-species competition among the Enterobacteriaceae in the inflamed gut. Moreover, we show that microcins can be narrow-spectrum therapeutics to inhibit enteric pathogens and reduce enterobacterial blooms.

P-selectin glycoprotein ligand-1 (PSGL-1) has long been studied as an adhesion molecule involved in immune cell trafficking and is recognized as a regulator of many facets of immune responses by myeloid cells. PSGL-1 also regulates T cell migration during homeostasis and inflammatory settings. However, recent findings indicate that PSGL-1 can also negatively regulate T cell function. As T cell differentiation is finely tuned by multiple positive and negative regulatory signals that appropriately scale the magnitude of the immune response, PSGL-1 has emerged as an important checkpoint during this process. Here we summarize what is known regarding PSGL-1 structure and function and highlight how it may act as an immune checkpoint inhibitor in T cells.

We recently demonstrated that PSGL-1 (P-selectin glycoprotein-1) could act as a T cell-intrinsic checkpoint inhibitor during chronic viral infection. As such, PSGL-1 may be a viable target to control T cell responses in the setting of autoimmune disease. In this study, we investigated the role of PSGL-1 on the activation of T cells and in mouse models of autoimmune disease. Here we find that the lack of PSGL-1 on T cells results in clinically worse disease in both EAE and adoptive transfer colitis, which supports its function as a negative regulator of T cell activation. However, in vivo treatment with an anti-PSGL-1 antibody known to block binding of the ligand, P-selectin, from the time of disease initiation had little effect on disease severity in the transfer colitis model and led to exacerbated disease in the EAE model. Crosslinking PSGL-1 on naïve T cells in vitro in the presence of TCR signals results in up-regulation of PD-1 but also up-regulation of other activation markers, suggesting that PSGL-1 exerts regulatory effects during the early activation program in T cells. Surprisingly, however, in an in vitro assay, crosslinking PSGL-1 on effector T cells resulted in resistance to regulatory T cell suppression. Therefore, anti-PSGL-1 treatment results in enhanced T cell activation and resistance to Treg suppression, thereby leading to more severe autoimmune disease by altering/blocking PSGL-1 signaling to phenocopy PSGL-1-deficiency.