Neighbourly help in the gut

Most of the IgA-secreting cells in the body are located in the intestine, and it is thought that the induction of class switching and targeting of these cells to the gut depends on signals from the gut-associated lymphoid tissue (GALT). But what are the signals that make a B cell home to the gut and specifically produce IgA? Mora et al. now show that the vitamin A metabolite retinoic acid produced by GALT-derived dendritic cells (DCs) confers gut tropism and, together with interleukin-6 (IL-6) or IL-5, induces IgA secretion.

DCs in the GALT, unlike DCs found in other lymphoid tissues, synthesize retinoic acid, which has been shown to induce the expression of a distinct set of trafficking molecules on the surface of T cells that infiltrate the gut. So, the authors examined the effect of GALT-derived DCs on expression of the gut-specific trafficking molecules α₄β₇-integrin and CC-chemokine receptor 9 (CCR9) on B cells. Co-culture of B cells with DCs derived from Peyer's patches resulted in α₄β₇-integrin^hiCCR9^hi B cells. By contrast, co-culture of B cells with DCs isolated from peripheral lymph nodes induced α₄β₇-integrin^lowCCR9^low B cells. Interestingly, expression of these homing molecules by B cells could be induced, in the absence of DCs, by exogenous retinoic acid. Therefore, only DCs from the GALT, through the secretion of retinoic acid, induce gut-tropic B cells.

The authors then examined the ability of these B cells to produce IgA. Only Peyer's patch-derived DCs induced de novo class switching and secretion of IgA by B cells. Blocking of the retinoic acid receptor with the receptor antagonist LE540 decreased IgA secretion in these co-cultures. However, retinoic acid alone was not sufficient to induce IgA secretion, indicating that, although retinoic acid is involved, additional factors are required. Blocking of IL-6 or IL-5 (cytokines that are known to induce IgA responses) with specific antibodies, together with LE540 (but not on their own), lead to a reduction in IgA secretion.

So, these data show that GALT-derived DCs directly induce gut tropism in a retinoic-acid-dependent manner, and they induce class switching to IgA in B cells through a synergistic mechanism that also involves retinoic acid. This study is of clinical relevance as it might explain why vitamin A deficiency exacerbates diarrhoeal disease in malnourished children.