MAIT cells in immune‐mediated tissue injury and repair Waterhölter, Alex; Wunderlich, Malte; Turner, Jan‐Eric
European journal of immunology,
December 2023, 2023-12-00, 20231201, Volume:
53, Issue:
12
Journal Article
Peer reviewed
Open access
Mucosal‐associated invariant T (MAIT) cells are T cells that express a semi‐invariant αβ T‐cell receptor (TCR), recognizing non‐peptide antigens, such as microbial‐derived vitamin B2 metabolites, ...presented by the nonpolymorphic MHC class I related‐1 molecule. Like NKT cells and γδT cells, MAIT cells belong to the group of innate‐like T cells that combine properties of the innate and adaptive immune systems. They account for up to 10% of the blood T‐cell population in humans and are particularly abundant at mucosal sites. Beyond the emerging role of MAIT cells in antibacterial and antiviral defenses, increasing evidence suggests additional functions in noninfectious settings, including immune‐mediated inflammatory diseases and tissue repair. Here, we discuss recent advances in the understanding of MAIT cell functions in sterile tissue inflammation, with a particular focus on autoimmunity, chronic inflammatory diseases, and tissue repair.
MAIT cells have dual functions in immune‐mediated tissue injury and repair. Depending on the context, MAIT cells can exacerbate inflammation and tissue injury by producing pro‐inflammatory cytokines and cytotoxic molecules or mediate tissue protection by regulating other immune cell subsets and secreting tissue repair factors.
Type 2 immune responses are essential in protection against intestinal helminth infections. In this study we show that IL-22, a cytokine important in defence against bacterial infections in the ...intestinal tract, is also a critical mediator of anti-helminth immunity. After infection with Nippostrongylus brasiliensis, a rodent hookworm, IL-22-deficient mice showed impaired worm expulsion despite normal levels of type 2 cytokine production. The impaired worm expulsion correlated with reduced goblet cell hyperplasia and reduced expression of goblet cell markers. We further confirmed our findings in a second nematode model, the murine whipworm Trichuris muris. T.muris infected IL-22-deficient mice had a similar phenotype to that seen in N.brasiliensis infection, with impaired worm expulsion and reduced goblet cell hyperplasia. Ex vivo and in vitro analysis demonstrated that IL-22 is able to directly induce the expression of several goblet cell markers, including mucins. Taken together, our findings reveal that IL-22 plays an important role in goblet cell activation, and thus, a key role in anti-helminth immunity.
IL-9 fate reporter mice established type 2 innate lymphoid cells (ILC2s) as major producers of this cytokine in vivo. Here we focus on the role of IL-9 and ILC2s during the lung stage of infection ...with Nippostrongylus brasiliensis, which results in substantial tissue damage. IL-9 receptor (IL-9R)-deficient mice displayed reduced numbers of ILC2s in the lung after infection, resulting in impaired IL-5, IL-13, and amphiregulin levels, despite undiminished numbers of Th2 cells. As a consequence, the restoration of tissue integrity and lung function was strongly impaired in the absence of IL-9 signaling. ILC2s, in contrast to Th2 cells, expressed high levels of the IL-9R, and IL-9 signaling was crucial for the survival of activated ILC2s in vitro. Furthermore, ILC2s in the lungs of infected mice required the IL-9R to up-regulate the antiapoptotic protein BCL-3 in vivo. This highlights a unique role for IL-9 as an autocrine amplifier of ILC2 function, promoting tissue repair in the recovery phase after helminth-induced lung inflammation.
Abnormal activation of the innate immune system is a common feature of autoimmune and chronic inflammatory diseases. Since their identification as a separate family of leukocytes, innate lymphoid ...cells (ILCs) have emerged as important effector cells of the innate immune system. Alterations in ILC function and subtype distribution have been observed in a variety of immune-mediated diseases in humans and evidence from experimental models suggests a subtype specific role of ILCs in the pathophysiology of autoimmune inflammation. In this review, we discuss recent advances in the understanding of ILC biology in autoimmune and chronic inflammatory disorders, including multiple sclerosis, inflammatory bowel diseases, psoriasis, and rheumatic diseases, with a special focus on the potential of ILCs as therapeutic targets for the development of novel treatment strategies in humans.
Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in ...autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell “reservoir” may present a therapeutic strategy for these autoimmune disorders.
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•Pathogenic TH17 cells migrate from the gut to the kidney in autoimmunity•TH17 cells egress the intestine in a S1PR1-dependent manner in glomerulonephritis•Targeting microbiota-induced TH17 cells ameliorates extraintestinal TH17 responses
By photolabelling intestinal cells, Krebs and colleagues provide direct evidence that microbiota-induced TH17 cells egress from the gut S1PR1-dependently and infiltrate the kidney via CCL20/CCR6 in immune-mediated diseases. This finding will build the basis for therapies targeting the intestinal TH17 cell “reservoir” to treat extraintestinal TH17 autoimmunity.
Innate lymphoid cells (ILCs) have an important role in the immune system's response to different forms of infectious and noninfectious pathologies. In particular, IL-5- and IL-13-producing type 2 ...ILCs (ILC2s) have been implicated in repair mechanisms that restore tissue integrity after injury. However, the presence of renal ILCs in humans has not been reported. In this study, we show that ILC populations are present in the healthy human kidney. A detailed characterization of kidney-residing ILC populations revealed that IL-33 receptor-positive ILC2s are a major ILC subtype in the kidney of humans and mice. Short-term IL-33 treatment in mice led to sustained expansion of IL-33 receptor-positive kidney ILC2s and ameliorated adriamycin-induced glomerulosclerosis. Furthermore, the expansion of ILC2s modulated the inflammatory response in the diseased kidney in favor of an anti-inflammatory milieu with a reduction of pathogenic myeloid cell infiltration and a marked accumulation of eosinophils that was required for tissue protection. In summary, kidney-residing ILC2s can be effectively expanded in the mouse kidney by IL-33 treatment and are central regulators of renal repair mechanisms. The presence of ILC2s in the human kidney tissue identifies these cells as attractive therapeutic targets for CKD in humans.
Tissue-Resident Lymphocytes in the Kidney Turner, Jan-Eric; Becker, Martina; Mittrücker, Hans-Willi ...
Journal of the American Society of Nephrology,
02/2018, Volume:
29, Issue:
2
Journal Article
Peer reviewed
Open access
It has become evident that nonlymphoid tissues are populated by distinct subsets of innate and adaptive lymphocytes that are characterized by minimal exchange with recirculating counterparts. ...Especially at barrier sites, such as the skin, gut, and lung, these tissue-resident lymphocyte populations are ideally positioned to quickly respond to pathogens and other environmental stimuli. The kidney harbors several classes of innate and innate-like lymphocytes that have been described to contribute to this tissue-resident population in other organs, including innate lymphoid cells, natural killer cells, natural killer T cells, mucosal-associated invariant T cells, and
T cells. Additionally, a substantial proportion of the adaptive lymphocytes that are found in the kidney displays a surface phenotype suggestive of tissue residency, such as CD69
CD4
T cells. In this review, we summarize recent advances in the understanding of tissue-resident lymphocyte populations, review the available evidence for the existence of these populations in the kidney, and discuss the potential physiologic and pathophysiologic roles thereof in kidney.
Innate lymphoid cells (ILCs) are important regulators of the immune response and play a crucial role in the restoration of tissue homeostasis after injury. GATA‐3+ IL‐13‐ and IL‐5‐producing group 2 ...innate lymphoid cells (ILC2s) have been shown to promote tissue repair in barrier organs, but despite extensive research on ILCs in the recent years, their potential role in autoimmune diseases is still incompletely understood. In the present study, we investigate the role of ILC2s in the MRL/MpJ‐Faslpr (MRL‐lpr) mouse model for severe organ manifestation of systemic lupus erythematosus (SLE). We show that in these MRL‐lpr mice, progression of lupus nephritis is accompanied with a reduction of ILC2 abundance in the inflamed renal tissue. Proliferation/survival and cytokine production of kidney‐residing ILC2s was suppressed by IFN‐γ and, to a lesser extent, by IL‐27 which were produced by activated T cells and myeloid cells in the nephritic kidney, respectively. Most importantly, restoration of ILC2 numbers by IL‐33‐mediated expansion ameliorated lupus nephritis and prevented mortality in MRL‐lpr mice. In summary, we show here that development of SLE‐like kidney inflammation leads to a downregulation of the renal ILC2 response and identify an ILC2‐expanding therapy as a promising treatment approach for autoimmune diseases.
Type 2 Innate lymphoid cell (ILC2) abundance in tissues is negatively regulated by T cell‐derived IFN‐γ and myeloid cells‐derived IL‐27 in chronic autoimmune inflammation. In a murine model of systemic lupus erythematosus, ILC2 numbers can be restored by IL‐33 therapy which ameliorates lupus nephritis and prolongs animal survival.
Immune cells infiltrating the tubulointerstitium critically contribute to the progression of chronic kidney disease. In this issue of Kidney international, Law et al. provide first evidence for a ...role of natural killer cells in the perpetuation of tubulointerstitial fibrosis in human renal disease. By detailed flow cytometric characterization of leukocytes isolated from kidney biopsies of chronic kidney disease patients, they define accumulation of natural killer cells as a feature of fibrotic kidney tissue and provide insight into potential mechanisms of how these cells might promote chronic kidney inflammation.
Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine ...IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1+ cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity.
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