Hai Qi

Major psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder, share overlapping genetic, neurodevelopmental, and neuroimmune underpinnings that challenge traditional diagnostic boundaries. This review synthesizes evidence across three interconnected domains: convergent genetic risk affecting synaptic and immune pathways, neurodevelopmental vulnerabilities shaped by early-life insults, and neuroimmune crosstalk involving blood–brain barrier dysfunction, sustained inflammation, and complement-mediated pathology. We propose a multidimensional developmental–immune framework in which genetic liability, environmental exposure timing, and peripheral immune status jointly shape transdiagnostic trajectories. This framework reframes psychiatric disorders as dynamic interactions among stable trait-like susceptibilities and fluctuating biological states, offering a roadmap for biomarker-driven stratification and early immune-targeted interventions.

Decoding which antigens activate a given T cell receptor (TCR) is a central challenge in immunology. We present SEEKER, a functional genome-scale library-on-library screening platform built on three elements: a Jurkat-derived T-APC cell (TAPCell) that combinatorially expresses one TCR and one peptide–MHC drawn from separate libraries together with an NFAT activation reporter; encapsulation of single TAPCells in a thermos-reversible hydrogel for isolated clonal expansion, so recognition is read out as intraclonal activation; and dual-asymmetric PCR that links TCR- and pMHC-encoding sequences into a heritable unit, enabling progressive hit enrichment over screening rounds. SEEKER interrogates ∼10 ⁸ TCR-pMHC combinations per run without prior knowledge. Screening joint-infiltrating CD8⁺ T cells from HLA-B*27⁺ ankylosing spondylitis patients against proteome-wide libraries validated 53 TCR– peptide pairs, uncovered extensive cross-recognition of self and common viral epitopes, and revealed highly polyreactive T cells recognizing up to 80 autoantigens, implicating virus-triggered poly-autoreactivity in multi-organ autoimmune diseases.

How a local infection triggers systemic humoral immunity remains unclear. Here we identify farnesyl pyrophosphate (FPP), a mevalonate pathway metabolic intermediate¹, as an endogenous alarmin that enhances IgG antibody responses through keratinocyte-derived IL-6 and CCL20. This signalling axis potentiates the differentiation of T follicular helper cells and migratory dendritic cells^2,3. FPP accumulates within keratinocytes after infection or ultraviolet irradiation through the activation of the mevalonate pathway mediated by the unfolded protein response–SREBF pathway, amplifying germinal centre (GC) responses in draining lymph nodes. Mechanistically, accumulated FPP in the cytosol engages transient receptor potential vanilloid 3 (TRPV3) by binding to its intracellular domains, inducing Ca²⁺ influx that subsequently activates the calmodulin–calcineurin–NFAT and PYK2–RAS–ERK pathways to enhance IL-6 and CCL20 production. This FPP–TRPV3–IL-6/CCL20–GC axis potentiates pathogen-specific antibody production, conferring protection in wild-type but not TRPV3-deficient mice. Single-cell RNA-sequencing analyses of systemic lupus erythematosus (SLE) skin lesions and pathogen-infected mouse skin demonstrate hyperactivation of this signalling axis, particularly in the TRPV3^high keratinocyte subset. In mouse models of SLE, the activation of this axis correlates with exacerbated disease pathology. Thus, FPP potentiates systemic humoral immunity through the TRPV3–IL-6/CCL20–GC signalling axis, providing insights for the development of vaccine adjuvants and potential therapeutics for SLE.

In the tumor microenvironment (TME), “exhausted” CD8+ T cells are classified into progenitor (Tpex) and terminally exhausted (Ttex) populations. Tpex cells, critically regulated by zinc finger and BTB domain containing 27 (Zbtb27)/Bcl6 transcription factor, could be reinvigorated during immune checkpoint blockade (ICB) therapy, while Ttex cells, characterized by stronger proliferation and cytotoxicity, play an indispensable role in tumor control. However, the mechanisms governing the differentiation into Ttex and their function remain not well understood. In this study, we identified that Zbtb32, highly expressed in CD8+ Ttex subset, is crucial for CD8+ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8+ T cells into Ttex subset, enhancing their cytotoxicity, proliferation, and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, especially in regulation of Id2 expression. Thus, our findings demonstrate the pivotal role of Zbtb32 in CD8+ T cell anti-tumor function, with implications in cancer immunotherapy.