Solstad et al. utilize a model of mouse-adapted SARS-CoV-2 to show that type III interferon signaling regulates DC function to promote SARS-CoV-2–specific CD8 T cell responses. The cover art shows images of murine lungs with broad distribution of SARS-CoV-2 nucleocapsid antigen in the absence of IFN-λ signaling following infection.
Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy linked to high-risk Human papillomavirus (HPV) infection, which develops from precursor lesions like Low-Grade Squamous Intraepithelial Lesions (LGSIL) and High-Grade Squamous Intraepithelial Lesions (HGSIL). ASCC incidence varies across populations, posing increased risk for People Living with HIV (PLWH). Our investigation focused on transcriptomic and metatranscriptomic changes from Squamous Intraepithelial Lesions (SILs) to ASCC. Metatranscriptomic analysis highlighted specific bacterial species (e.g., Fusobacterium nucleatum, Bacteroides fragilis) more prevalent in ASCC than precancerous lesions. These species correlated with gene encoding enzymes (Acca, glyQ, eno, pgk, por) and oncoproteins (FadA, dnaK), presenting potential diagnostic or treatment markers. Unsupervised transcriptome analysis identified distinct sample clusters reflecting histological diagnosis, immune infiltrate, HIV/HPV status, and pathway activities, recapitulating anal cancer progression's natural history. Our study unveiled molecular mechanisms in anal cancer progression, aiding in stratifying HGSIL cases based on low- or high-risk progression to malignancy.
Ezequiel Lacunza, Valeria Fink, María E. Salas, Ana M. Gun, Jorge A. Basiletti, María Alejandra Picconi, Mariano Golubicki, Juan Robbio, Mirta Kujaruk, Soledad Iseas, Sion L. Williams, María Figueroa, Omar Coso, Pedro Cahn, Juan C. Ramos, Martin C. Abba
HLA-B*27 was one of the first HLA alleles associated with an autoimmune disease, i.e., axial spondyloarthritis (axSpA) and acute anterior uveitis (B27AAU), which cause joint and eye inflammation, respectively. Gastrointestinal inflammation has been suggested as a trigger of axSpA. We recently identified a bacterial peptide (YeiH) that can be presented by HLA-B*27 to expanded public T cell receptors (TCRs) in the joint in axSpA and the eye in B27AAU. While YeiH is present in enteric microbiota and pathogens, additional evidence that pathogenic T cells in HLA-B*27-associated autoimmunity may have had a prior antigenic encounter within the gastrointestinal tract remains lacking. Here, we analyze ocular, synovial, and blood T cells in B27AAU and axSpA, showing that YeiH-specific CD8 T cells express a mucosal gene set and surface proteins consistent with intestinal differentiation, including CD161, integrin α4β7, and CCR6. In addition, we find an expansion of YeiH-specific CD8 T cells in the blood of axSpA and B27AAU over healthy controls, whereas influenza-specific CD8 T cells were equivalent across groups. Lastly, we demonstrate the dispensability of TRBV9 for antigen recognition. Collectively, our data suggest that, in HLA-B27-associated autoimmunity, early antigen exposure and differentiation of pathogenic CD8 T cells may occur in enteric organs.
Michael A. Paley, Xinbo Yang, Lynn M. Hassman, Frank Penkava, Lee I. Garner, Grace L. Paley, Nicole Linskey, Ryan Agnew, Paulo Henrique Arantes de Faria, Annie Feng, Sophia Y. Li, Davide Simone, Elisha D.O. Roberson, Philip A. Ruzycki, Ekaterina Esaulova, Jennifer Laurent, Lacey Feigl-Lenzen, Luke E. Springer, Chang Liu, Geraldine M. Gillespie, Paul Bowness, K. Christopher Garcia, Wayne M. Yokoyama
Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in Infancy (SAVI). SAVI patients develop interstitial lung disease (ILD) and produce autoantibodies that are commonly associated with systemic autoimmune diseases. Mice expressing the most common SAVI mutation STING V154M (VM) similarly develop ILD, but exhibit severe T and B cell lymphopenia, low serum Ig titers, and lack autoantibodies. Importantly, lethally irradiated VM hosts reconstituted with wildtype (WT) stem cells (WT→VM) still develop ILD. In this study, we find that WT→VM chimeras had restored B cell function, produced autoantibodies, and thereby recapitulated the loss of tolerance seen in SAVI patients. Lymphocytes derived from both WT and BCR or TCR transgenic (Tg) donors accumulated in the extravascular lung tissue of WT+Tg→VM mixed chimeras, but lymphocyte activation and germinal center formation required WT cells with a diverse repertoire. Furthermore, when T cells isolated from the WTVM chimeras were adoptively transferred to naïve Rag1-deficient 2º hosts, they trafficked to the lung and recruited neutrophils. Overall, these findings indicated that VM expression by radioresistant cells promoted the activation of autoreactive B cells and T cells that then differentiated into potentially pathogenic effector subsets.
Kevin MingJie Gao, Kristy Chiang, Sharon Subramanian, Xihui Yin, Paul J. Utz, Kerstin Nündel, Kate A. Fitzgerald, Ann Marshak-Rothstein
Type 2 diabetes (T2D) is on the rise worldwide and is associated with various complications of the oral cavity. Using an adult-onset diabetes preclinical model, we demonstrated profound periodontal alterations in T2D mice, including inflamed gingiva, disintegrated periodontal ligaments (PDL), marked alveolar bone loss, and unbalanced bone remodeling due to decreased formation and increased resorption. Notably, we observed elevated levels of the Wnt signaling inhibitor sclerostin in the alveolar bone of T2D mice. Motivated by these findings, we investigated whether a sclerostin-neutralizing antibody (Scl-Ab) could rescue the compromised periodontium in T2D mice. Administering Scl-Ab subcutaneously once a week for four weeks, starting four weeks after T2D induction, led to substantial increases in bone mass. This effect was attributed to the inhibition of osteoclasts and promotion of osteoblasts in both control and T2D mice, effectively reversing the bone loss caused by T2D. Furthermore, Scl-Ab stimulated PDL cell proliferation, partially restored the PDL fibers, and mitigated inflammation in the periodontium. Our study thus established a T2D-induced periodontitis mouse model characterized by inflammation and tissue degeneration. Scl-Ab emerged as a promising intervention to counteract the detrimental effects of T2D on the periodontium, exhibiting limited side effects on other craniofacial hard tissues.
Hakan Turkkahraman, Shannan Flanagan, Tianli Zhu, Nisreen Akel, Silvia Marino, Dayane Ortega-Gonzalez, Xue Yuan, Teresita M. Bellido
Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases; however, effective drug treatments are still lacking. The formation of neutrophil extracellular traps (NETs) has been shown to be crucial trigger of AAA and identifying upstream regulatory targets is thus key to discovering therapeutic agents for AAA. We revealed that phosphoinositide 3-kinase gamma (PI3Kγ) acted as an upstream regulatory molecule, and that PI3Kγ inhibition reduced NET formation and aortic wall inflammation, thereby markedly ameliorating AAA. However, the mechanism of NET formation regulated by PI3Kγ remains unclear. In this study, we showed that PI3Kγ deficiency inactivated the noncanonical pyroptosis pathway, which suppressed downstream NET formation. In addition, PI3Kγ regulation of noncanonical pyroptosis was dependent on cAMP/protein kinase A (cAMP/PKA) signaling. These results clarify the molecular mechanism and crosstalk between PI3Kγ and NETosis in the development of AAA, potentially facilitating the discovery of therapeutic options for AAA.
Yacheng Xiong, Shuai Liu, Yu Liu, Jiani Zhao, Jinjian Sun, Yongqing Li, Baihong Pan, Wei Wang