Nat Immunol︱Daily maintenance, a new mechanism for tissue monitoring under local T cell homeostasis

Article | Sister Xian For a long time, people's role of the immune system has been limited to anti-infection and anti-tumor protection.
It is believed that the steady-state immune system has always been in a quiescent state and can only be awakened when infected
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However, as research progresses, this traditional view is gradually being changed, and it is not only discovered that the immune response occurs in non-microbial situations, but also that the homeostatic immune system helps maintain metabolism, memory and barrier integrity.
Many of these interactions occur locally, involving immune cells permanently associated with non-lymphoid tissues [1,2]
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While macrophages are well-established regulators of tissue state, lymphocytes have been found to play an increasing role in this process, so whether antigen receptors on lymphocytes can be used to sense tissue as they recognize foreign antigens What about internal disturbances? One of these lymphocytes of high interest is the intraepithelial lymphocyte (IEL), which constitutes one of the largest T cell compartments and is often implicated in tissue stress monitoring, but its mechanisms are currently poorly understood
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IELs are differentially conserved across multiple tissues in different species and are disproportionately enriched in γδ T cells expressing the site-specific T-cell antigen receptor (TCR)
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This selective enrichment reflects the developmental dependence of IELs on homologous tissue-specific, epithelial-expressed butyrophilin-like (BTNL) heteromers, such as the selectivity for two PD-L1-like members of the BTNL family, Skint1 and Skint2 Regulates Vγ5Vδ1+ IEL in mice
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It has been found that while Skint1 and Skint2 mediate the development of Vγ5Vδ1+ precursors in the thymus, they can also be expressed by suprabasal keratinocytes (KCs), where mature Vγ5Vδ1+ IELs can persist
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So how do they continue to affect the function of mature IELs? How does the locally aggregated Vγ5Vδ1+ TCR participate in KC and its signaling at steady state? Recently, Adrian C.
Hayday's team from the Francis Crick Institute in the United Kingdom published an article online in Nature Immunology entitled "Normality sensing licenses local T cells for innate-like tissue surveillance, using Vγ5Vδ1+ IEL (also known as dendrites).
Epidermal T cells (DETC) to study how tissue T cells use TCR to distinguish between normal and stressful states, and found that macromolecular aggregates of γδ T cell antigen receptors in the epidermis of mice are associated with and dependent on Skint1, while This TCR-mediated "normal sensing" was shown to be closely related to the characteristic phenotype and epidermal barrier function of γδ T cells, but also to the ability of intraepidermal T cells to respond to T cells by using intrinsic tumor necrosis factor (TNF) superfamily receptors.
Subsequent tissue perturbation responds rapidly, while disrupting the Skint1-dependent interaction between local γδ T cells and KCs at homeostasis increases susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation
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first demonstrated that in the epidermal layer of FVB mice, most DETCs aggregated into clusters and TCRs within these clusters could co-localize with actin, whereas FVB.
Tac mice expressing truncated, non-functional Skint1 and Trgv5–/–Trdv4–/– mice (both strains lack the canonical Vγ5Vδ1+ DETC), the frequency of DETCs without TCR-actin colocalization was significantly increased
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Furthermore, when in FVB.
When wild-type Skint1 was overexpressed in Tac mice, the co-localization of TCR-actin was restored to a level similar to that in wild-type mice (Fig.
1); whereas when wild-type FVB mice were given intradermal injection of Skint1-specific monoclonal antibody At 2G2, the aggregation frequency of TCR-actin was significantly reduced
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This confirms that the Vγ5Vδ1 TCR is required for juxta-epithelial TCR aggregation and that Skint1 is required for the establishment and maintenance of juxta-epithelial TCR aggregation
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Further experiments revealed that Skint1 maintained the TCR-mediated interaction between DETC and KC at steady state, which in turn determined the epidermal localization of Skint1
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Figure 1 Subsequently, the researchers injected Skint1 antibody or control intradermally into the ears of FVB mice weekly for 10 weeks to observe the effect of sustained in situ destruction of Skint1
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The experimental results showed that the number and frequency of Vγ5Vδ1+ DETC in mice were comparable to the number and frequency of major histocompatibility complex class II-positive (MHCII+) Langerhans cells (LC), indicating that the maintenance of long-term DETC populations is independent of on Skint1
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However, the researchers also found that the functional role of DETC on effective epidermal integrity was significantly affected by Skint1 blockade independent of LC
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The ears of Skint1 antibody-treated mice exhibited moderate inflammation, increased transcutaneous water loss (TEWL), persistently decreased expression of epidermal DETC-derived barrier maintenance cytokines and KC genes involved in epidermal barrier formation, and increased KC apoptosis
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Further single-cell sequencing of CD45+ MHCII-EpCAM- epidermal lymphocytes from wild-type FVB mice treated with Skint1 antibody for 7 days identified four types of DETC cell populations (cluster 0-cluster 3), suggesting that although The anatomical localization of DETCs and TCR expression were nearly identical, but heterogeneous
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The cell population in cluster 3, although small, is rich in mRNAs for lymphocyte activation and co-stimulation (such as 4-1BB) as well as effector molecules, which represent a response in DETC to the occasional mild skin perturbation at steady state (combing or scratching) a subset of which responded positively, whereas Skint1 antibody treatment selectively reduced cluster 3, suggesting that skint1 sensing is required for sustained activation of a small subset of DETCs (cluster 3) at steady state
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In addition, regardless of cell clustering, gene expression in DETCs was more extensively altered after Skint1 antibody treatment, and the analysis revealed that the intrinsic activation state of most DETCs depends on persistent Skint1-dependent DETC–KC interactions
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In-depth analysis revealed that epidermal Skint1 at steady state facilitates immune surveillance by maintaining a predetermined effector phenotype in most DETCs and by supporting the activation of a small subset of DETCs
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To further elucidate the role of Skint1 in immune surveillance, the researchers irradiated the ears of C57BL/6 mice with UVR to induce DNA damage
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The results showed a substantial reduction in near-epithelial TCR aggregation following UVR irradiation and a rapid pleiotropic change in gene expression compared to the unirradiated control group
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Furthermore, UVR leads to the upregulation of many genes encoding potential effector molecules
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Subsequently, mice were given an intradermal injection of Skint1 antibody before UVR, and DETCs were sorted and analyzed 24 hours after UVR irradiation.
The readiness of DETC to respond to UVR is maintained
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Further experimental results show that signaling through the TNF receptor is a non-redundant component of the rapid DETC response to skin radiation and is dependent on the prior permission of the Skint1–TCR interaction, and that Skint1 induction at homeostasis can be Regulation of DETC responsiveness to different stimuli
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Furthermore, regardless of mutagenic epidermal stress or non-mutagenic epidermal stimulation, Skint1 promotes rapid DETC effector responses that naturally limit inflammatory damage and impairment of functional barrier integrity
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Taken together, the present study found that the interaction between DETC and KC mediated by Vγ5Vδ1+ TCR at steady state involves and is dependent on Skint1, and this crosstalk does not significantly regulate tissue residency of DETC nor does it require DETC to populate the epidermis.
However, this is critical for DETC function, and disruption of Skint1 sensing impedes DETC maintenance of epidermal homeostasis, interferes with homeostatic immune surveillance signals, and impairs DETC efficient responsiveness to epithelial stress
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Since the Skint1-dependent DETC–KC interaction occurs at homeostasis, this mode of tissue immune monitoring can be considered as 'normal induction'
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Indeed, TCR-dependent, Skint1-dependent interaction with KC through TNF receptors confers an innate-like responsiveness to DETC, thereby limiting histopathology after injury including UVR and chemical stimuli, with important implications of clinical significance
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Original link: https://doi.
org/10.
1038/s41590-021-01124-8 Publisher: Eleven References 1.
Zmora, N.
, Bashiardes, S.
, Levy, M.
& Elinav, E.
The role of the immune system in metabolic health and disease.
Cell Metab.
25, 506–521 (2017).
2.
Vivier, E.
et al.
Innate lymphoid cells: 10 years on.
Cell 174, 1054–1066 (2018).
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