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Long-lived tissue-resident memory T cells (T RM cells) confer fast, robust protection after pathogen rechallenge. Gebhardt and colleagues show that skin T RM cells arise from KLRG1 – cells that differentiate in situ in response to IL-15 and TGF-β. Tissue-resident memory T cells (T RM cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103 + CD8 + T RM cells developed in the skin from epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T RM cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.

Tissue-resident memory T cells (T RM cells) provide rapid frontline protection from reinfection. Bergsbaken and Bevan identify a gut T RM cell population generated via an unconventional pathway that is protective against a natural mouse intestinal pathogen. We report that oral infection with Yersinia pseudotuberculosis results in the development of two distinct populations of pathogen-specific CD8 + tissue-resident memory T cells (T RM cells) in the lamina propria. CD103 − T cells did not require transforming growth factor-β (TGF-β) signaling but were true resident memory cells. Unlike CD103 + CD8 + T cells, which were TGF-β dependent and were scattered in the tissue, CD103 − CD8 + T cells clustered with CD4 + T cells and CX3CR1 + macrophages and/or dendritic cells around areas of bacterial infection. CXCR3-dependent recruitment of cells to inflamed areas was critical for development of the CD103 − population and pathogen clearance. Our studies have identified the 'preferential' development of CD103 − T RM cells in inflammatory microenvironments within the lamina propria and suggest that this subset has a critical role in controlling infection.

The Immunological Genome Project aims to build a comprehensive database of gene-expression and gene-regulatory networks in the mouse immune system. Here Turley and colleagues analyze the transcriptomes of lymph-node stromal cells under steady-state and inflammatory conditions. Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly elucidated. Here, comparative transcriptomic analyses of mouse LNSC subsets demonstrated the expression of important immune mediators, growth factors and previously unknown structural components. Pairwise analyses of ligands and cognate receptors across hematopoietic and stromal subsets suggested a complex web of crosstalk. Fibroblastic reticular cells (FRCs) showed enrichment for higher expression of genes relevant to cytokine signaling, relative to their expression in skin and thymic fibroblasts. LNSCs from inflamed lymph nodes upregulated expression of genes encoding chemokines and molecules involved in the acute-phase response and the antigen-processing and antigen-presentation machinery. Poorly studied podoplanin (gp38)-negative CD31 − LNSCs showed similarities to FRCs but lacked expression of interleukin 7 (IL-7) and were identified as myofibroblastic pericytes that expressed integrin α 7 . Together our data comprehensively describe the transcriptional characteristics of LNSC subsets.

The integrin α (ITGA) subfamily genes play a fundamental role in various cancers. However, the potential mechanism and application values of ITGA genes in adipogenic differentiation of human adipose-derived stem cells (hADSCs) remain elusive. This study confirmed that ITGA2/3/5 mRNA expressions were repressed during adipogenesis. Blockade of ITGA2/3/5 enhanced adipogenic differentiation of hADSCs. Oil red O staining found that more lipid droplets were apparent in the ITGA2/3/5 inhibition group following 14 d adipogenic induction than in the control group. In addition, inhibition of ITGA2/3/5 promoted the expression of adipogenesis-related genes (PPAR-γ, C/EBPα, FABP4). Mechanistically, ITGA2/3/5 functioned by regulating the Rac1 signaling pathway, which reasonably explains ITGA2/3/5’s role in adipogenic differentiation of hADSCs. Our studies suggest that blockades of ITGA2/3/5 promote the adipogenic differentiation of hADSCs.

Cancer‐associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer–stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non‐small‐cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC‐associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer–stroma interactions may serve as a novel, promising anti‐tumor strategy. Here, we analyzed gene expression profiles of non‐small‐cell lung cancer‐associated fibroblasts (CAFs). TGF‐β1 induced production of fibronectin and collagen type I in the cancer stroma, which next promoted the combined expression of integrin α11 and collagen type XI α1 in CAFs. Integrin α11+/collagen type XI α1+ CAFs relocalized within the cancer stroma in a fibronectin‐ and collagen type I‐dependent manner and promoted cancer cell migration.

Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29 (β1-integrin), CD44, CD49d (α4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.

While effective in specific settings, adoptive chimeric antigen receptor (CAR) T cell therapy for cancer requires further improvement and optimization. Our previous results show that CD40L-overexpressing CAR T cells mobilize endogenous immune effectors, resulting in improved antitumor immunity. However, the cell populations required for this protective effect remain to be identified. Here we show, by analyzing Batf3 −/− mice lacking the CD103 + conventional dendritic cell type 1 (cDC1) subpopulation important for antigen cross-presentation, that CD40L-overexpressing CAR T cells elicit an impaired antitumor response in the absence of cDC1s. We further find that CD40L-overexpressing CAR T cells stimulate tumor-resident CD11b − CD103 − double-negative (DN) cDCs to proliferate and differentiate into cDC1s in wild-type mice. Finally, re-challenge experiments show that endogenous CD8 + T cells are required for protective antitumor memory in this setting. Our findings thus demonstrate the stimulatory effect of CD40L-overexpressing CAR T cells on innate and adaptive immune cells, and provide a rationale for using CD40L-overexpressing CAR T cells to improve immunotherapy responses. CD40L-expressing chimeric antigen receptor (CAR) T cells show enhanced anti-tumor immunity, but the cellular mechanisms are still unclear. Here we show, by analyzing mice deficient of conventional dendritic cell type 1 (cDC1) that cDC1s are induced by CD40L + CAR T cells to prime endogenous CD8 T cells for a stronger anti-tumor immune response.

Immune mechanisms contribute to the neuropathology of Alzheimer’s disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8 + T cell compartment is dysregulated in AD patients and in the 3xTg-AD mouse model, accumulating activated CD103 – tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103 – CD8 + T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain CD103 – CD8 + T cells in 3xTg-AD mice ameliorates cognitive decline and reduces neuropathology. GrK induces neuronal dysfunction and tau hyperphosphorylation in human and mouse cells via protease-activated receptor-1 (PAR-1), which is expressed at higher levels in the AD brain, revealing a key immune-mediated neurotoxic axis. We conclude that communication between CD8 + T cells and the nervous system is altered in AD, paving the way for therapies targeting T cell-dependent neurotoxic inflammation. Neuroimmune communication in Alzheimer’s disease (AD) is poorly understood. Here, the authors show that CD103–CD8+ resident memory T cells induce neurotoxicity and neuroinflammation in AD via the granzyme K–PAR-1 axis.

CD11d/CD18 is the most recently discovered and least understood β2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration – two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under unique transcriptional control and expressed on a sub-set of predominately tissue-differentiated innate leukocytes. The following review is the first to capture the nearly three decades of CD11d research and discusses the emerging role of CD11d in leukocyte migration and retention during the progression of a staged immune response.

Clonal deletion through negative selection is critical to eliminate autoreactive T cells in the thymus. Negative selection, however, is imperfect such that some autoreactive thymocytes can escape thymic deletion and successfully populate peripheral tissues. This is also the case for autoreactive 2D2 TCR transgenic T cells, a widely employed mouse model in studying the pathogenesis of CD4 T cell-mediated experimental autoimmune encephalomyelitis. How autoreactive 2D2 thymocytes evade negative selection, however, remains incompletely understood. Here we show that negative selection of MHC-II-restricted thymocytes, specifically 2D2 TCR transgenic T cells, is associated with the induction of integrin CD103, and that forced expression of CD103 downregulates CXCR4 expression, alters intra-thymic trafficking, and reinforces clonal deletion of immature thymocytes. Stratification of positively versus negatively selected 2D2 T cells based on their distinct coreceptor expression further shows that CD103 does not affect the generation of conventional CD4 T cells but is deleterious for autoreactive CD4, CD8 double-negative 2D2 T cells that correspond to CD69-negative CCR7-intermediate thymocytes, displaying markers of agonistic TCR signalling. Collectively, these results propose CD103 expression as an indicator and contributor of negative selection for MHC-II-restricted T cells, providing further mechanistic insights into the process of T cell selection in the thymus. Clonal deletion is an important mechanism for the elimination of autoreactive T cells, however, negative selection of thymocytes is imperfect. Here authors show that MHC-II-restricted thymocytes avoid negative selection via downregulation of the integrin CD103, altering intra-thymic trafficking and distribution in a way that favours their survival.