Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells

Abstract

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.

Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles

“…The majority (50%) of memory CD8 + T cells synthesizing antiviral cytokines in response to ex vivo influenza virus infection were within the Trm cell subset ( Figure 4, B and C), highlighting the potent capacity of this memory subset to rapidly generate effector cytokines in response to influenza virus infection within human lung tissue. This is consistent with recent reports that human lung tissue resident memory cells constitutively express deployment-ready mRNAs encoding effector molecules, which is reflective of these cells being poised for rapid responsiveness (11).…”

“…The cytotoxic activity of Trm cells was assessed by measuring CD107a, granzyme B, and perforin probeing poised for rapid responsiveness (11). Whether the human lung contains influenza-specific CD8 + Trm cells and whether these cells have a role in modulating the course of the disease is currently unknown.…”

Human Tissue-Resident Memory T Cells Are Defined by Core Transcriptional and Functional Signatures in Lymphoid and Mucosal Sites

“…Transcriptional profiling has been reported for mouse CD8 + TRM in which CD8 + memory T cells isolated from a barrier site (skin, intestine or lung) were compared with spleen Mackay et al, 2013). In human studies, CD8 + TRM isolated based on CD103 expression from individual tissues (lung, skin) have been profiled in comparison to blood subsets (Cheuk et al, 2017;Hombrink et al, 2016). Here, we employed an innovative and comprehensive approach to assess differences in putative circulating and resident populations within tissues by directly comparing CD69 + memory subsets from a lymphoid and mucosal site (spleen and lung) with the corresponding CD69 − subset from each tissue as well as CD69 − TEM from blood for both CD4 + and CD8 + lineages.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…69 In addition, Notch signaling and Notch inducing transcription factor EGR2 are up-regulated in CD103 + lung T RM cells and essential for the formation and maintenance of lung T RM cells. 70,71 The survival of CD103 + , but not CD103 − lung T RM requires IL-15 signaling. 60 Interestingly, Notch may promote the maintenance of lung T RM cells via an IL-15-independent and metabolism-related mechanism.…”

“…60 Interestingly, Notch may promote the maintenance of lung T RM cells via an IL-15-independent and metabolism-related mechanism. 70 …”