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-γ (IFNγ) 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.