The inflammatory microenvironment influences dendritic cell-mediated antigen presentation to regulate asthma Th2 inflammation. The scavenger receptor is expressed on DCs and regulates antigen presentation and T priming. However, whether the transmembrane scavenger receptor (SR-PSOX/CXCL16) regulates the phenotype and antigen presentation function of DCs remains unclear. We found that CXCL16 is mainly expressed on DCs in the lung tissues of asthma patients and asthma mice. CXCL16 knockout led to the suppression of airway inflammation, mucus overproduction, and airway hyperresponsiveness in Aspergillus-induced asthma. In addition, the adoptive transfer of Aspergillus-pulsed DCs shows the CXCL16+ DCs exerted a promoting role in airway inflammation, the CXCL16- DCs inhibit airway inflammation. Additionally, RNA sequencing and flow cytometry data revealed that CXCL16 knockout inhibits airway inflammation by suppressing the antigen processing and presentation function of DCs, which was mediated by MHC II chaperone H2-DM. Furthermore, we found CXCL16 knockout suppressed dendritic cells differentiated forward to cDC2b subtype which is mainly charged with antigen presentation to T cell. In conclusion, we found that CXCL16 downregulated the capacity of DC antigen processing and presentation to suppress airway inflammation by reducing H2-DM expression which mediated DC differentiation. The study suggested that inhibition of CXCL16 can be a potential therapy for asthma.
© 2025. The Author(s).

Antigen-specific regulation of T cell response is crucial for limiting hyperimmune response. In this study, we discovered that antibodies specific to the antigen peptide-MHC class II complex are produced during helper T cell responses to various antigens. These antibodies specifically inhibited T cell receptor (TCR) recognition of MHC class II molecules presenting specific antigen peptide. We have termed these antibodies ‘immuneinduced TCR-like antibodies’ (iTabs). Immunization with peptides containing flanking residues induced iTabs, whereas immunization with peptides lacking flanking residues did not. Furthermore, immunization of iTab-inducible peptide as well as iTab treatment suppressed autoimmune disease development. Our findings provide a strategy for suppressing antigen-specific helper T cell responses using specific peptides, potentially controlling autoimmune diseases.

Specific MHC class II alleles are strongly associated with susceptibility to various autoimmune diseases. Although the primary function of MHC class II molecules is to present peptides to helper T cells, MHC class II molecules also function like a chaperone to transport misfolded intracellular proteins to the cell surface. In this study, we found that autoantibodies in patients with Graves' disease preferentially recognize thyroid-stimulating hormone receptor (TSHR) complexed with MHC class II molecules of Graves' disease risk alleles, suggesting that the aberrant TSHR transported by MHC class II molecules is the target of autoantibodies produced in Graves' disease. Mice injected with cells expressing mouse TSHR complexed with MHC class II molecules, but not TSHR alone, produced anti-TSHR autoantibodies. These findings suggested that aberrant self-antigens transported by MHC class II molecules exhibit antigenic properties that differ from normal self-antigens and abrogate self-tolerance, providing a novel mechanism for autoimmunity.

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4+ T cells into naive syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). The development of EAE lesions is initiated when transferred CD4+ T cells access the CNS and are reactivated by local antigen-presenting cells (APCs) bearing endogenous myelin peptide/MHC class II complexes. The identity of the CNS-resident, lesion-initiating APCs is widely debated. Here we demonstrate that classical dendritic cells (cDCs) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APCs in their ability to stimulate naive, as well as effector, myelin-specific T cells to proliferate and produce proinflammatory cytokines directly ex vivo. cDCs expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDCs led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDCs, and the factors that regulate them, be further investigated as potential therapeutic targets in MS.