Antigen-presenting cells (APC) tailor immune responses to microbial encounters by stimulating differentiation of CD4 T cells into the Th1 and Th2 lineages. We demonstrate that APC use the Notch pathway to instruct T cell differentiation. Strikingly, of the two Notch ligand families, Delta induces Th1, while Jagged induces the alternate Th2 fate. Expression of these different Notch ligands on APC is induced by Th1- or Th2-promoting stimuli. Th2 differentiation has been considered a default process as APC-derived instructive signals are unknown. We demonstrate that Jagged constitutes an instructive signal for Th2 differentiation, which is independent of IL4/STAT6. Th2 differentiation induced by APC is abrogated in T cells lacking the Notch effector RBPJkappa. Notch directs Th2 differentiation by inducing GATA3 and by directly regulating il4 gene transcription through RBPJkappa sites in a 3' enhancer.
Tissue-resident memory T cells (T cells) in the airways mediate protection against respiratory infection. We characterized T cells expressing integrin α (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung T cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint. A distinct set of transcription factors was active in CD103 T cells, including Notch. Genetic and pharmacological experiments with mice revealed that Notch activity was required for the maintenance of CD103 T cells. We have thus identified specialized programs underlying the residence, persistence, vigilance and tight control of human lung T cells.
Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts1–6. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts7. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen associated molecular patterns (PAMPs), which serve to alert the immune system8,9, are present in both live and killed vaccines, suggesting that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA (mRNA) as a vita-PAMP present only in viable bacteria, recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even nonpathogenic bacteria in sterile tissues can trigger similar responses, provided they are alive. Thus, the immune system actively gauges the infectious risk by scouring PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers an alert mode not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.
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