CD103hi lung-resident regulatory T cells constrain the fibrotic responses induced by CD103low tissue-resident pathogenic CD4 T cells
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ABSTRACT: Tissue-resident memory T (TRM) cells are crucial mediators of adaptive immunity in non-lymphoid tissues. However, the functional heterogeneity and pathogenic roles of CD4+ TRM cells that reside within chronic inflammatory lesions remain unknown. We found that CD69hiCD103low CD4+ TRM cells produced effector cytokines and promoted the inflammation and fibrotic responses induced by chronic exposure to Aspergillus fumigatus. Simultaneously, immunosuppressive CD69hiCD103hiFoxp3+ CD4+ regulatory T (Treg) cells were induced and constrained the ability of pathogenic CD103low TRM cells to cause fibrosis. Thus, lung tissue-resident CD4+ T cells play crucial roles in the pathology of chronic lung inflammation, and CD103 expression defines pathogenic effector and immunosuppressive tissue-resident cell subpopulations in the inflamed lung.
Project description:Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation.
Project description:Resident memory T-cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. While lung CD8+ TRM have been extensively characterized, the properties of CD4+ TRM remain unclear. Here we determined the transcriptional signature of CD4+ TRM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4+ TRM, while expression of tissue egress and lymph node homing molecules were low. CD103+ TRM expressed low levels of T-bet, only a small portion expressed Eomes, and while the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103+ TRM showed a Notch signature. CD4+CD103+ TRM constitutively expressed high transcript levels of numerous cytotoxic mediators, which was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be due to an accessible IFNγ locus and was partially due to rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4+ TRM in the human lung. Understanding the specific properties of CD4+ TRM is required to rationally improve vaccine design.
Project description:CD103hi lung-resident regulatory T cells constrain the fibrotic responses induced by CD103low tissue-resident pathogenic CD4 T cells
Project description:Current cancer immunotherapies promote recovery of CD103+ tissue-resident memory T cells (Trm) population of the tumor-infiltrating T lymphocytes (TILs). However, not all treated patients exhibit improved anti-tumor immunity and survival, likely due to the immunophenotypical diversity among the CD103+ Trm TILs. Utilising multifaceted proteomics approaches and patients’ clinical analyses, we discovered an unusual subset of CD8+ Trm TILs expressing non-canonical integrin β3 early during T cells activation. The integrin β3 surprisingly heterodimerises with CD103 on T cells, leading to unconventional granulysin-mediated cytotoxicity, elevated alternative bioenergy usage and efficient T cell migration, with minimal overall exhaustion. Importantly, early-stage non-small cell lung carcinoma (NSCLC) patients with enriched presence of integrin β3+CD103+ Trm TILs exhibited better clinical prognosis, with improved T cell immunophenotype, hence confirming the beneficial role of this unusual subset of Trm TILs. These unconventional anti-tumor T cell features provide new avenues and future opportunities for designing better translational immunotherapy strategies.
Project description:In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process
Project description:In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (TRM) represent a potentially important cellular player in this process
Project description:Tissue-resident memory T cells (Trm) are central to maintaining autoimmune and inflammatory disease. Modulation of their continued replenishment in tissues has significant implications for clinical treatment. In a murine model of lung inflammation, scRNA-seq revealed the complexity of antigen-responding CD4+ Trm, encompassing many pathogenic subpopulations including Th2, Th17, Th1 and CTL, but suggested several targets for therapeutic intervention, with significant co-expression of the costimulatory molecules OX40, ICOS, CD30, and CD30L throughout these T cells. Inhibiting ICOSL alone, or co-blocking OX40L and CD30L, with neutralizing antibodies, only partially suppressed the response of Trm to recall antigen, whereas inhibiting all three molecules strongly reduced the accumulation of Trm-derived effector memory T cells, and ablated all aspects of lung inflammation. Most importantly, transient therapeutic inhibition of these molecules together prevented the continued accumulation and long-term persistence of induced Trm, leading to a state of tolerance such that subsequent exposure to antigen failed to re-establish a pathogenic inflammatory response. These data show that costimulatory molecules are critical for reactivation and persistence of pathogenic CD4+ Trm, and reveal several therapeutic combinations that are applicable for treatment of lung inflammatory disease and potentially multiple autoimmune diseases.
Project description:Tissue-resident memory T cells (Trm) are central to maintaining autoimmune and inflammatory disease. Modulation of their continued replenishment in tissues has significant implications for clinical treatment. In a murine model of lung inflammation, scRNA-seq revealed the complexity of antigen-responding CD4+ Trm, encompassing many pathogenic subpopulations including Th2, Th17, Th1 and CTL, but suggested several targets for therapeutic intervention, with significant co-expression of the costimulatory molecules OX40, ICOS, CD30, and CD30L throughout these T cells. Inhibiting ICOSL alone, or co-blocking OX40L and CD30L, with neutralizing antibodies, only partially suppressed the response of Trm to recall antigen, whereas inhibiting all three molecules strongly reduced the accumulation of Trm-derived effector memory T cells, and ablated all aspects of lung inflammation. Most importantly, transient therapeutic inhibition of these molecules together prevented the continued accumulation and long-term persistence of induced Trm, leading to a state of tolerance such that subsequent exposure to antigen failed to re-establish a pathogenic inflammatory response. These data show that costimulatory molecules are critical for reactivation and persistence of pathogenic CD4+ Trm, and reveal several therapeutic combinations that are applicable for treatment of lung inflammatory disease and potentially multiple autoimmune diseases.
Project description:Leishmaniasis causes a significant disease burden worldwide. Although Leishmania-infected patients become refractory to reinfection following disease resolution, effective immune protection has not yet been achieved by human vaccines. While circulating Leishmania-specific T cells are known to play a critical role in immunity, the role of memory T cells present in peripheral tissues has not been explored. Here, we identify a population of skin-resident Leishmania-specific memory CD4+ T cells. These cells produce IFNγ, and remain resident in the skin when transplanted by skin graft onto naïve mice. They function to recruit circulating T cells to the skin in a CXCR3 dependent manner, resulting in better control of the parasites. Our findings are the first to demonstrate that CD4+ TRM cells form in response to a parasitic infection, and indicate that optimal protective immunity to Leishmania, and thus the success of a vaccine, may depend on generating both circulating and skin-resident memory T cells. Two conditions were analyzed. For each condition, four mice were used, resulting in eight samples in total.
Project description:Chronic lung allograft dysfunction (CLAD) significantly limits long-term survival following lung transplantation. To identify potential targets for CLAD prevention, T cells from explanted CLAD lungs and lung-draining lymph nodes, as well as diseased and non-diseased controls were isolated and single-cell RNA sequencing and TCR sequencing were performed. TCR sequencing revealed a clonally expanded population of tissue resident memory (TRM) CD8+ T cells with high cytotoxic potential including upregulation KLRK1, encoding the co-receptor NKG2D. These cytotoxic CD8+ TRM accumulated around the CLAD airways and had 100-fold increase in clonal overlap with lung draining lymph nodes when compared to non-CLAD lungs. Using a murine model of orthotopic lung transplant, we confirmed that cytotoxic CD8+ TRM accumulation was due to chronic rejection and not transplant alone. Furthermore, blocking NKG2D in-vivo attenuated the airway remodeling following transplantation and diminished airway accumulation of CD8+ T cells. Our findings support NKG2D as a potential therapeutic target for CLAD, affecting cytotoxic CD8+ TRM accumulation.