Innate control of IgA

IgA is important for protecting against intestinal pathogens and maintaining a healthy gut flora. But it is not known exactly how it is regulated. New data published in Science show that soluble and membrane-bound forms of the cytokine lymphotoxin (LT) that are produced by innate lymphoid cells (ILCs) control the induction of IgA through distinct mechanisms.

Credit: NPG

LT occurs in trimeric soluble (LTα₃) or membrane-bound (LTα₁β₂) forms. Previous studies have shown a crucial role for membrane-bound LTα₁β₂ on ILCs in the generation of IgA through the formation of isolated lymphoid follicles (ILFs). So the authors were surprised to find that mice with a specific ablation of LTβ in retinoic acid receptor-related orphan receptor-γt-expressing (RORγt⁺) cells (ILCs and double-positive thymocytes) lacked ILFs but had normal fecal IgA levels and only slightly reduced blood IgA levels compared with wild-type controls. By contrast, deletion of the gene encoding LTα in RORγt⁺ cells led to a marked decrease in both fecal and blood IgA levels. This reduction in IgA levels altered the composition of the commensal bacteria: segmented filamentous bacteria were increased and Bacteroidetes were reduced in LTα mutant mice compared with controls. Consistent with a role for soluble LTα₃ in intestinal IgA production, mice lacking its receptors — tumour necrosis factor receptor 1 (TNFR1) or TNFR2 — had reduced IgA levels.

ILC-derived soluble LTα₃ controls IgA induction through regulation of T cell homing to the lamina propria

When mice that lacked LTβ in ILCs were also made T cell deficient, IgA production was abrogated, suggesting that T cells are required to mediate IgA class switching in the absence of membrane-bound LTα₁β₂. Indeed, reconstitution of these animals with wild-type or CD40 ligand (CD40L)-deficient T cells confirmed the involvement of CD40–CD40L signalling in T cell-dependent IgA class switching mediated by soluble LTα₃. Further experiments suggested that ILC-derived soluble LTα₃ controls IgA induction through regulation of T cell homing to the lamina propria.

Finally, in mice with LTα₁β₂-deficient ILCs, dendritic cells expressed lower levels of inducible nitric oxide synthase and were less potent in inducing IgA in vitro. This suggests that membrane-bound LTα₁β₂ on ILCs controls T cell-independent IgA production through the regulation of dendritic cells.

So, ILC-derived soluble and membrane-bound LTs — acting through T cell-dependent and T cell-independent mechanisms, respectively — organize adaptive immune responses in the gut and control the commensal composition.