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This review gives an overview of the protective role of CD8+ T cells in SARS-CoV-2 infection. The cross-reactive responses intermediated by CD8+ T cells in unexposed cohorts are described. Additionally, the relevance of resident CD8+ T cells in the upper and lower airway during infection and CD8+ T-cell responses following vaccination are discussed, including recent worrisome breakthrough infections and variants of concerns (VOCs). Lastly, we explain the correlation between CD8+ T cells and COVID-19 severity. This review aids in a deeper comprehension of the association between CD8+ T cells and SARS-CoV-2 and broadens a vision for future exploration.

Abstract The innate immune system serves as the body's first line of defense, utilizing pattern recognition receptors like Toll‐like receptors to detect pathogens and initiate rapid response mechanisms. Following this initial response, adaptive immunity provides highly specific and sustained killing of pathogens via B cells, T cells, and antibodies. Traditionally, it has been assumed that innate immunity activates adaptive immunity; however, recent studies have revealed more complex interactions. This review provides a detailed dissection of the composition and function of the innate and adaptive immune systems, emphasizing their synergistic roles in physiological and pathological contexts, providing new insights into the link between these two forms of immunity. Precise regulation of both immune systems at the same time is more beneficial in the fight against immune‐related diseases, for example, the cGAS–STING pathway has been found to play an important role in infections and cancers. In addition, this paper summarizes the challenges and future directions in the field of immunity, including the latest single‐cell sequencing technologies, CAR‐T cell therapy, and immune checkpoint inhibitors. By summarizing these developments, this review aims to enhance our understanding of the complexity interactions between innate and adaptive immunity and provides new perspectives in understanding the immune system.

Abstract Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA‐bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF‐1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8‐deficient patients.

The serine/threonine-specific protein kinases (STKs) are important for cell survival, proliferation, differentiation, and apoptosis. In B cells, these kinases play indispensable roles in regulating important cellular functions. Multiple studies on human and other animal cells have shown that multiple STKs are involved in different stages of B cell development and antibody production. However, how STKs affect B cell development and function is still not completely understood. Considering that B cells are clinically important in immunity and diseases, our understanding of STKs’ roles in B cells is in great need of investigation with current technologies. Investigating serine/threonine kinases will not only deepen our insight into B cell-related disorders but also facilitate the identification of more effective drug targets for conditions like lymphoma and systemic lupus erythematosus.

Abstract IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1β inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.