For T cells, variety is the spice of life: CD4 ⁺ helper T cells come in a variety of flavors. This allows them to respond in a manner that is tailored to the pathogen they encounter. Becattini et al. wondered whether multiple “flavors” of human CD4 ⁺ T cells respond to specific stimuli or if just one flavor dominates. To find out, they stimulated human memory CD4 ⁺ T cells with a fungus, a bacteria, or a vaccine antigen. Multiple helper cell subsets participated in each response. T cell receptor sequencing revealed that in some cases, T cells with the same specificity acquired different helper cell fates. Thus, there is more heterogeneity in human T cell responses than previously appreciated. Science , this issue p. 400

Listeria monocytogenes is a foodborne pathogen that causes septicemia, meningitis and chorioamnionitis and is associated with high mortality. Immunocompetent humans and animals, however, can tolerate high doses of L. monocytogenes without developing systemic disease. The intestinal microbiota provides colonization resistance against many orally acquired pathogens, and antibiotic-mediated depletion of the microbiota reduces host resistance to infection. Here we show that a diverse microbiota markedly reduces Listeria monocytogenes colonization of the gut lumen and prevents systemic dissemination. Antibiotic administration to mice before low dose oral inoculation increases L. monocytogenes growth in the intestine. In immunodeficient or chemotherapy-treated mice, the intestinal microbiota provides nonredundant defense against lethal, disseminated infection. We have assembled a consortium of commensal bacteria belonging to the Clostridiales order, which exerts in vitro antilisterial activity and confers in vivo resistance upon transfer into germ free mice. Thus, we demonstrate a defensive role of the gut microbiota against Listeria monocytogenes infection and identify intestinal commensal species that, by enhancing resistance against this pathogen, represent potential probiotics.

Significance: To design an effective subunit vaccine, it is essential to identify the most relevant protective antigen. One way to achieve this goal is to analyze, at the clonal level, the human antibody response and identify the molecules targeted by the most effective neutralizing antibodies. Here we provide an example of this approach in the case of human cytomegalovirus (HCMV), a pathogen causing severe disease in newborns and immunosuppressed individuals. Through the analysis of the human antibody response to HCMV, we identified the gHgLpUL128L pentamer as the target of the most potent neutralizing antibodies and demonstrated that a pentamer vaccine elicited in mice extremely high levels of HCMV neutralizing antibodies. This example illustrates a general approach to develop subunit vaccines against complex pathogens.