Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines

Bhattacharjee, A.; Burr, A. H. P.; Overacre-Delgoffe, A. E.; Tometich, J. T.; Yang, D.; Huckestein, B. R.; Linehan, J. L.; Spencer, S. P.; Hall, J. A.; Harrison, O. J.; Morais da Fonseca, D.; Norton, E. B.; Belkaid, Y.; Hand, T. W.

doi:10.1101/2020.06.03.130831

bioRxiv · 10.1101/2020.06.03.130831

Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines

Bhattacharjee, A.·Burr, A. H. P.·Overacre-Delgoffe, A. E.·Tometich, J. T.·Yang, D.·Huckestein, B. R.·Linehan, J. L.·Spencer, S. P.·Hall, J. A.·Harrison, O. J.·Morais da Fonseca, D.·Norton, E. B.·Belkaid, Y.·Hand, T. W.

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Abstract

Environmental Enteric Dysfunction (EED) is an intestinal disease caused by malnutrition and infection that leads to malabsorption and stunting. EED is also associated with a reduced efficacy of oral vaccines. We show in a microbiota and diet-dependent model of EED that oral vaccine-specific CD4+ T cell responses fail in the small intestine but responses in the draining lymph node were unaffected. Accordingly, the number of immunosuppressive ROR{gamma}T+FOXP3+ Tregs in the small intestine inversely correlated with the response to oral vaccination. Depletion of ROR{gamma}T+FOXP3+ Tregs indicated that they were necessary for EED-associated inhibition of the vaccine response. Additionally, ROR{gamma}T+FOXP3+ Tregs are important to regulate EED-associated inflammation as their depletion significantly worsened stunting. We have shown that EED-associated intestinal inflammation leads to a localized intestinal blockade of CD4 T cell immunity. These results support a modular model for immunity where tissue responses can be regulated independently of systemic immunity to prevent autoinflammation.

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Bhattacharjee, A., Burr, A. H. P., Overacre-Delgoffe, A. E., Tometich, J. T., Yang, D., Huckestein, B. R., Linehan, J. L., Spencer, S. P., Hall, J. A., Harrison, O. J., Morais da Fonseca, D., Norton, E. B., Belkaid, Y., Hand, T. W.. 2020-06-03. Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines. https://doi.org/10.1101/2020.06.03.130831

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