Trigger-happy resident memory CD4+ T cells inhabit the human lungs

Resident memory T cells (T-RM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. Although lung CD8(+) T-RM have been extensively characterized, the properties of CD4(+) T-RM remain unclear. Here we determined the transcriptional signature of CD4(+) T-RM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4(+) T-RM, whereas expression of tissue egress and lymph node homing molecules were low. CD103(+) T-RM expressed low levels of T-bet, only a small portion expressed Eomesodermin (Eomes), and although the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103(+) T-RM showed a Notch signature. CD4(+) CD103(+) T-RM constitutively expressed high transcript levels of numerous cytotoxic mediators that was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be because of an accessible interferon-c (IFN gamma) locus and was partially because of rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4(+) T-RM in the human lung. Understanding the specific properties of CD4(+) T-RM is required to rationally improve vaccine design.