CD8+ tissue-resident memory T (TRM) cells in the epidermis are part of a highly sensitive sentinel system that can rapidly respond to previously encountered pathogens. Their formation requires transforming growth factor-β (TGFβ), an abundant cytokine with broad functions in the immune system. It had been assumed that CD8+ TRM cells develop locally in the skin from uncommitted CD8+ memory precursor T cells. However, a report in Science now shows that T cells are preconditioned for epithelial TRM fate at a much earlier developmental stage: that is, as naive T cells, which are presented with TGFβ during encounters with migratory dendritic cells (mDCs) in lymph nodes.
TGFβ is secreted in a latent form in a complex that includes latency-associated peptide (LAP). It becomes activated when LAP binds to members of the αV class of integrin molecules, which facilitate the release of active TGFβ. Mani et al. generated mice that lacked αV integrin expression in DCs (αV-ΔDC mice) and observed a selective loss of epithelial CD8+ TRM cells, indicating that the activation of TGFβ by DCs is crucial for the formation of these cells.
Interestingly, when ex vivo activated ovalbumin (OVA)-specific effector CD8+ T cells (OT-I cells) were injected into these mice, they were able to migrate to epidermal sites of inflammation and differentiate into TRM cells. This indicated that DC-activated TGFβ is not required for the differentiation of effector CD8+ T cells into TRM cells.
Instead, the authors hypothesized that DC-activated TGFβ may act at an earlier stage and precondition naive CD8+ T cells in secondary lymphoid organs for enhanced TRM cell formation. They tested this by injecting αV-ΔDC and wild-type mice with naive OT-I cells and then vaccinating them with an OVA-expressing plasmid. They found that vaccination straight after cell transfer resulted in equal numbers of epithelial TRM cells in wild-type and αV-ΔDC mice, whereas vaccination 3 weeks after cell transfer resulted in lower numbers of epithelial TRM cells in the latter. This indicated that the capacity of naive CD8+ T cells to form epithelial TRM cells decreases over time when DCs are unable to activate TGFβ.
Further analysis of naive CD8+ T cells from wild-type and αV-ΔDC mice revealed differences in chromatin accessibility, particularly in regions enriched for binding motifs of certain transcription factors. In naive CD8+ T cells from wild-type mice, these regions were enriched in binding motifs for the RUNX family of transcription factors, including RUNX3, which is known to be a positive regulator of epithelial TRM cell differentiation. This implied that epigenetic changes driving epithelial TRM cell differentiation occur before T cell activation.
In order to determine where this epigenetic preconditioning takes place, the authors analysed mice that lack lymph nodes and mice deficient in mDCs, a type of DC that, at steady state, migrates from peripheral tissues into draining lymph nodes but is absent from the spleen. In both cases, the preconditioning of naive CD8+ T cells for epithelial TRM cell fate was impaired. This was also the case in mice where DCs did not co-express MHC class I (MHC-I) molecules and αV integrin, leading to the conclusion that the preconditioning of naive CD8+ T cells involves non-cognate, but MHC-I-dependent and αV integrin-dependent, physical interactions of the T cells with mDCs in lymph nodes, during which the naive T cells are presented with active TGFβ. This also exemplifies how a widely abundant cytokine can have very localized and specific functions.
“preconditioning of naive CD8+ T cells involves non-cognate, but MHC-I-dependent and αV integrin-dependent, physical interactions of the T cells with mDCs”
In contrast to the general assumption that the naive T cell population is relatively uniform in its potential to differentiate into different effector and memory cell subsets, the study shows that naive CD8+ T cells are preconditioned during steady state to efficiently form epidermal TRM cells upon antigen encounter. The authors point out that this may have important implications for vaccine development, where optimized preconditioning might enhance vaccine-induced protection. Conversely, in conditions such as psoriasis where epithelial TRM cells play a pathogenic role, one could envisage therapeutic approaches that interfere with preconditioning for TRM cell fate.
Mani, V. et al. Migratory DCs activate TGF-β to precondition naïve CD8+ T cells for tissue-resident memory fate. Science 366, eaav5728 (2019)
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Flemming, A. Naive T cells can be primed for tissue residency. Nat Rev Immunol 19, 718–719 (2019). https://doi.org/10.1038/s41577-019-0239-z