Research Article

Migratory DCs activate TGF-β to precondition naïve CD8+ T cells for tissue-resident memory fate

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Science  11 Oct 2019:
Vol. 366, Issue 6462, eaav5728
DOI: 10.1126/science.aav5728

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Some naïve T cell fates are sealed

Tissue-resident memory T (TRM) cells constitute a subpopulation of memory cells that reside in tissues instead of recirculating. CD8+ epithelial TRM (eTRM) cells, which occupy the epithelium of sites like the skin, require transforming growth factor–β (TGF-β) for their development. Mani et al. found that αV integrin–expressing dendritic cells, which activate and present TGF-β, are key (see the Perspective by Farber). Surprisingly, this interplay did not occur in the skin or draining lymph nodes during T cell priming. Rather, resting naïve CD8+ T cells interacted with αV integrin–expressing migratory dendritic cells during immune homeostasis, reversibly preconditioning them to become eTRM cells upon activation. A potent cytokine is thus controlled in a context-dependent manner and preimmune T cell repertoires may be less uniform than previously presumed.

Science, this issue p. eaav5728; see also p. 188

Structured Abstract


Successful immune responses to infections generate memory T cells that provide enhanced protection from reinfection by the same pathogen. Some memory cells continually recirculate through tissues via the blood and lymph, whereas others establish local residence. This second population includes CD8+ tissue-resident memory T cells that seed the epithelial layers of barrier tissues (eTRM cells), such as the skin. These cells constitute a highly sensitive sentinel system, which responds to reencounters with cognate pathogen-derived antigens by triggering a local inflammatory response to rapidly contain the infection. The formation of eTRM cells requires transforming growth factor β (TGF-β), a broadly expressed cytokine with a wide range of functions in the immune system. Secreted TGF-β is abundant in tissues, but its biological activity is tightly regulated by release of the active cytokine from the latent pro-complex. Binding to αV-integrins facilitates TGF-β release for activity in the immune system. However, the cellular mechanisms of its release, as well as the sites of CD8+ T cell exposure driving the formation of eTRM cells, are unknown.


Enhancing eTRM cell formation is desirable in the context of vaccines designed to protect against pathogens that infect by way of barrier tissues. Conversely, attenuating eTRM cell formation may be therapeutic for diseases, such as psoriasis, in which eTRM cells play pathogenic roles. Understanding how TGF-β is activated and where it acts on T cells to enable eTRM differentiation may inform new approaches to selectively amplify or disrupt this process without the predicted systemic effects of globally perturbing TGF-β activity. We hypothesized that αV-integrin–expressing dendritic cells (DCs) activate and present TGF-β to CD8+ T cells to enable eTRM cell formation.


Upon deleting αV integrins from CD11c+ DCs in mice, we observed a pronounced reduction in the number of CD8+ T cells in the epidermis, whereas the numbers of dermal CD8+ T cells and other skin immune cells were unchanged. The same selective defect was apparent after different forms of skin immune challenge, including DNA vaccination, indicating that the de novo formation of eTRM cells was disrupted. Unexpectedly, neither expression of αV integrins on DCs in skin-draining lymph nodes during priming of T cell responses, nor on DCs in the skin, was required for generation of eTRM cells. Instead, the exposure of resting naïve CD8+ T cells to αV-expressing DCs during immune homeostasis preconditioned them for effective formation of eTRM cells upon activation. An examination of the genomic accessibility of naïve cells suggested that TGF-β signals enabled by αV-expressing DCs prime genes involved in eTRM cell formation for their more rapid induction. This reversible preconditioning effect was mediated by migratory DCs and occurred in lymph nodes, but not in spleen, as both exposure of naïve T cells to TGF-β and the formation of eTRM cells in the skin were strongly impaired in the absence of lymph nodes or of CCR7-dependent DC migration from skin to lymph nodes. eTRM formation was also reduced when expression of major histocompatibility complex class I (MHC I) molecules and αV integrins was segregated on individual DCs, indicating that exposure of naïve CD8+ T cells to TGF-β occurs in the context of noncognate, yet MHC I–dependent, physical interactions with migratory DCs.


Naïve CD8+ T cells are preconditioned for the formation of skin eTRM cells by DCs that migrate from nonlymphoid tissues to lymph nodes at steady state. These DCs both activate and present TGF-β to naïve T cells, exemplifying how this cytokine’s potent biological activities can be limited to specific contexts through its requirement for extracellular processing. In this way, individual T cells appear to be actively preconditioned for a specific differentiation path already at the naïve cell stage. This is in contrast to the general expectation that the preimmune T cell repertoire is uniform in its potential to differentiate into various effector and memory cell subsets upon activation.

Migratory DCs activate TGF-β in lymph nodes to precondition naïve CD8+ T cells for eTRM cell formation.

During homeostasis, migratory DCs that express αV integrins, including αVβ8, but not resident DCs, activate TGF-β and present it to naïve CD8+ T cells (TN) during noncognate interactions. Preconditioned naïve T cells then effectively become epithelial resident memory T (eTRM) cells upon immune challenge.


Epithelial resident memory T (eTRM) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eTRM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8+ T cells and prepares them for the formation of eTRM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I–dependent interactions with peripheral tissue–derived migratory dendritic cells (DCs) and depends on DC expression of TGF-β–activating αV integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.

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