Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4+ TRM cells with a TH17 signature (termed TRM17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal TRM17 cells were induced by pathogens infecting the kidney, such as Staphylococcus aureus, Candida albicans, and uropathogenic Escherichia coli, and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney TRM17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced TRM17 cells have a previously unrecognized function in aggravating autoimmune disease.
The human thymus is susceptible to viral infections that can severely alter thymopoiesis and compromise the mechanisms of acquired tolerance to self-antigens. In humans, plasma cells residing primarily in the bone marrow confer long-lasting protection to common viruses by secreting antigen-specific antibodies. Since the thymus also houses B cells, we examined the phenotypic complexity of these thymic resident cells and their possible protective role against viral infections. Using tissue specimens collected from subjects ranging in age from 5 days to 71 years, we found that starting during the first year of life, CD138+ plasma cells (PC) begin accumulating in the thymic perivascular space (PVS) where they constitutively produce IgG without the need for additional stimulation. These, thymic PC secrete almost exclusively IgG1 and IgG3, the two main complement-fixing effector IgG subclasses. Moreover, using antigen-specific ELISpot assays, we demonstrated that thymic PC include a high frequency of cells reactive to common viral proteins. Our study reveals an unrecognized role of the PVS as a functional niche for viral-specific PCs. The PVS is located between the thymic epithelial areas and the circulation. PCs located in this compartment may therefore provide internal protection against pathogen infections and preserve the integrity and function of the organ.
Our study reveals a high frequency of infiltrating B cells around the coronary arteries of allografts with CAV, independent of DSA or AMR. These cells are enriched for innate B cells with a polyreactive profile. The findings shift the focus from conventional DSA-producing B cells to the potentially pathogenic polyreactive B cells in the development of clinical CAV.
Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1 for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.
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