Mucosal Immunology最新文献

Natural Killer (NK) cells are cytotoxic lymphocytes and key mediators of innate immunity, essential for combating viral infections and cancer. Notably, they exhibit immunological memory, generating a stronger response upon re-exposure to the same stimulus. While NK cell memory holds promise for infection control, its role in bacterial infections remains poorly understood. Previously, we demonstrated that Streptococcus pneumoniae induces long-term, specific, and protective NK cell memory. In this study, we performed single-cell RNA-seq to uncover how NK cells respond to S. pneumoniae infection. Our findings reveal that challenged Memory (cMemory) NK cells undergo transcriptional reprogramming following S. pneumoniae infection and have a differential transcriptional response upon reinfection. In addition, we identified distinct cMemory NK cell subpopulations, with responding cMemory NK cells displaying a general enhanced activation, proliferation, and cytotoxic activity. These findings support a novel role for NK cells in the context of bacterial infections, thereby opening avenues for harnessing the potential of innate immune memory for therapeutic applications.

Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition affecting the gastrointestinal tract. It is characterised by epithelial and immunological dysfunctions, including alterations in populations of Innate Lymphoid Cells (ILCs), including tissue-resident RORγt-expressing Group 3 ILCs (ILC3s). ILC3s contribute to the maintenance of intestinal homeostasis by closely interacting with both the epithelium and adaptive immune cells. Here, we reveal that murine and human ILC3s modulate these interactions through Transforming Growth Factor-Beta 1 (TGF-β1), a pleiotropic cytokine secreted in an inactive form. We show that ILC3s synthesise and activate latent TGF-β1 through mechanical and proteolytic pathways. ILC3s aid the induction of FoxP3⁺ regulatory T cells via TGF-β1 and promote a regenerative transcriptional signature in intestinal epithelial cells. The downstream impact of ILC3-derived TGF-β1 is conserved between mouse and humans, but the TGF-β1 activators expressed by ILC3 differ between the species. In IBD, where ILC3s are reduced in the inflamed intestinal regions, TGF-β1-production and activation machinery remains intact in ILC3s, suggesting this pathway is functional in disease and could be targeted to enhance intestinal homeostasis through promotion of epithelial regeneration and induction of regulatory T cells.

Germinal centres (GCs) in mucosal tissues such as the nasal associated lymphoid tissue (NALT) generate high-affinity antibodies critical for protective, and in some cases, sterilising immunity. Therefore, initiation of GCs at the respiratory mucosa is of tremendous clinical significance in the development of mucosal vaccines. However, GC initiation in NALT is limited in part by a scarcity of CD4⁺ T follicular helper (T_FH) cells, and the tolerogenic environment in the NALT. Here, we identify a critical role for Natural Killer T (NKT) cells with a follicular helper-like phenotype (NKT_FH) in driving NALT GC formation. Unlike their systemic counterparts, mucosal NKT cells evade anergy after repeated stimulation and remain poised to provide early cognate B cell help to CD1d-presented antigens. We show that NKT_FH provide IL-21, allowing for GC recruitment and functionally substituting for a pre-expanded CD4⁺ T_FH pool. These findings reveal a previously unrecognised NKT-dependent mechanism of GC seeding in the NALT and suggest that inclusion of an NKT cell agonist into intranasal vaccines could overcome GC entry bottlenecks and enhance high-affinity antibody responses.