Unravelling immunoregulatory circuits of tissue inflammation

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

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Abstract

In the past years we had shown that cell-autonomous Complement is produced both from immune and non-immune cells and delineated the major pathways of their induction, notably LFA-1-induced signals in T cells and type I interferons in respiratory epithelial cells. These findings were important because they indicated that inflamed tissues, which are unable to access plasma-circulating complement, actually represent a complement-rich environment, the complement here being derived from both immune and non-cells. We thus hypothesized that studying transcriptomes of Complement-activated T cells would reveal the effects of Complement on T cells. We showed that Complement induces a self-contained autocrine/paracrine vitamin D (VitD) system in T cells that is required for appropriate inflammatory T cell shut-down, permitting tissue healing to take place. Briefly, we found that Complement induced a cell-intrinsic VitD system permitting T cells to both activate and respond to VitD. Sensing of active VitD caused genome-wide epigenetic changes that generated new and augmented existing super-enhancers, and recruited key TFs (principally VDR, c-JUN, STAT3 and BACH2) that shaped the VitD response in T cells. We found, as we had done before, that BACH2 was a central TF in these events. T cells of patients with COVID-19 showed Th1 hyper-activation and evidence of dysregulation of this VitD shut-down program, indicating either a lack of substrate (VitD deficiency) and/or abnormal regulation of this system. These data may explain the epidemiologic link between vitamin D insufficiency/deficiency and risk of both developing COVID-19 and suffering mortality after infection. They are also noteworthy because they establish cross-regulation between the two main interests of our lab, Complement and the TF BACH2. We found that this system was operational in psoriatic skin and dysregulated in cells from patients with Job and BRIDA syndromes. As part of a collaboration with colleagues in the UK we also showed that activated Vitamin D represses glycolytic programs in effector CD4+ T cells to repress inflammatory functions. This paper was published in Nature Immunology. Through a collaboration with the Portilla and Lionakis labs, respectively, we also demonstrated that the Complement C5 system is also key to activation of myeloid cells in the kidneys that drive tissue scarring following acute kidney injury (the folic acid model) and that C5 is essential for anti-fungal immunity. Thus, C5 antagonism in humans and mice predisposes to invasive fungal diseases. These findings were published in the American Journal of Physiology and Cell, respectively. In parallel, with the Lazarevic lab, we showed that the transcription factor EGR2 is essential for promoting pathogenic potential in Th17 cells, which then mediate autoimmune brain inflammation. These findings were published in Nature Immunology. These were supplemented with a collaboration with the Mathe group in NCATS, with whom we showed using data from the N3C dataset that patients with pre-existing autoimmunity and/or on immunosuppressive medication were significantly more at risk of developing severe COVID-19 after infection with SARS-CoV2. This was published in Clinical Infectious Diseases. We also collaborated with the Lionakis lab on a publication in the New England Journal of Medicine demonstrating the JAK inhibitors can be beneficial for patients with APECED syndrome. This was a direct follow-on from our prior collaboration detailing this pathway published in Science. Our work on transcriptional regulators of T cells culminated in two review articles delineating the roles of non-coding RNAs in autoimmunity in T cells (published in the Journal of Autoimmunity) and the role of transcription factors in shaping regulatory T cell identify (published in Nature Reviews Immunology). This has been followed up by a primary paper under review detailing the role of one novel enhancer RNA in regulating key aspects of T cell biology. This has since been followed up by several publications and preprints. First, we reported that super-silencers are crucial for development and carcinogenesis in B cells (Nat Commun, in press, 2025). Separately, we contributed to work demonstrating a PI3Kδ–Foxo1–FasL signaling amplification loop that rewires CD4+ T helper cell signaling, differentiation, and epigenetic remodeling (bioRxiv, 2024). Our complement research advanced substantially this year. We published mechanistic insights into intracellular complement (complosome) and broader conceptual opportunities and challenges for this field in JACI and JCI reviews. We also collaborated on an Immunity study showing that a CD4⁺ T cell-intrinsic C5aR2–prostacyclin–IL-1R2 axis orchestrates Th1 contraction, further linking complement biology to adaptive immunity. Finally, in addition to our work in complement biology, we developed the Benchmark platform and Pathway Ensemble Tool (PET)in collaboration with Dr Kazemian's group at Purdue. These tools integrate multiple computational methods to identify disease-relevant biological pathways from omics data, reducing researcher bias and providing unbiased insights. PET has successfully identified novel prognostic pathways, biomarkers, and therapeutic drugs across various cancers. Notably, it highlighted CCT068127, a CDK2/9 inhibitor, as highly effective against bladder cancer, outperforming current treatments in lab and animal models. This was published in Nature Communications. Both Benchmark and PET are available online, offering valuable resources for improving the understanding and treatment of complex diseases.