Natural Killer T follicular helper cell function permits germinal centre entry in nasal associated lymphoid tissue

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.