Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life

Koch MA, Reiner GL, Lugo KA, Kreuk LS, Stanbery AG, Ansaldo E, Seher TD, Ludington WB, Barton GM.

Photo of authors of this paper.

From left: Emily Brock, Lieselotte Kreuk, Alison Stanbery, Olivia Majer, Bethany Russell, Gregory Barton, Jacques Deguine, Allison Roberts, Kyler Lugo, April Price. Eduard Ansaldo, Meghan Koch, Thaddeus Seher, Zachary Newman, Bo Lui. Not pictured: William Ludington and Gabrielle Reiner.

Immediately following birth, the gastrointestinal tract is colonized by diverse microbial species. Establishing proper immune responses to these microbes is essential to ensure optimal growth and overall health during the neonatal development period. Along with commensal microbes, mammalian mothers provide nutrients and immunomodulatory factors to their young through breast milk. By comparing offspring of antibody sufficient and deficient mothers, we found that antibodies derived from breast milk were required to limit mucosal effector CD4+ T cell responses in neonatal mice. Within breast milk, IgA is the most abundant antibody isotype, and IgA antibodies have long been appreciated to mediate host-commensal mutualism. Surprisingly, we observed that young mice lacking maternal IgA did not exhibit the same phenotype as mice lacking all maternal antibodies indicating that other antibody isotypes present in breast milk help dampen mucosal T cell immunity.

We developed a flow cytometry assay to profile the complete anti-commensal antibody response and found, surprisingly, that in addition to IgA, healthy mice produce IgG antibodies specific for commensal microbes. Further characterization revealed that these antibodies are primarily composed of the IgG2b and IgG3 isotypes and are elicited by a pathway independent of T cells, yet dependent on signaling through innate immune receptors, Toll-like receptors (TLR) 2 and 4. Young mice contained high concentrations of maternally derived IgG2b and IgG3 antibodies, prompting us to test whether these antibodies were important in regulating mucosal T cell responses.  Lactating mothers utilize the neonatal Fc receptor (FcRn) to transport IgG but not IgA antibodies into breast milk. Accordingly, pups of FcRn-deficient mothers had reduced levels of anti-commensal IgG2b and IgG3 antibodies, however these pups did not display heightened mucosal T cell responses. We postulated that maternal IgA may compensate for the lack of maternally acquired IgG to regulate mucosal effector T cells. Consistent with this, we observed that progeny of mothers doubly deficient in IgA and FcRn contained increased numbers of mucosal effector CD4+ T cells similar to mice lacking all maternally-derived antibodies.

To assess the consequences of this immune dysregulation, we characterized the CD4+ T effector response and found that maternal antibody-deficient mice displayed enhanced accumulation of T follicular helper (Tfh) cells within mucosal sites. Tfh cells serve important roles in promoting B cell responses. In line with this, we found increased numbers of germinal center B cells, a cell phenotype defined by being engaged in the generation of a T-dependent antibody responses, in progeny of antibody-deficient dams compared to control offspring. Additionally, we observed that mice lacking maternal antibodies weighed significantly less than control offspring and were slightly more susceptible intestinal disease development at early time points, however these differences resolved with age. Cumulatively, this data supports a model whereby acquisition of maternally derived anti-commensal IgA and T-independent IgG antibodies dampens mucosal T cell responses in early life. In the absence of these maternal antibodies, we propose that a compensatory T-dependent antibody response ensues to restore intestinal homeostasis.

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