Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells
Alexander Visekruna, Sabrina Hartmann, Yasmina Rodriguez Sillke, Rainer Glauben, Florence Fischer, Hartmann Raifer, Hans Mollenkopf, Wilhelm Bertrams, Bernd Schmeck, Matthias Klein, Axel Pagenstecher, Michael Lohoff, Ralf Jacob, Oliver Pabst, Paul William Bland, Maik Luu, Rossana Romero, Britta Siegmund, Krishnaraj Rajalingam, Ulrich Steinhoff
Alexander Visekruna, Sabrina Hartmann, Yasmina Rodriguez Sillke, Rainer Glauben, Florence Fischer, Hartmann Raifer, Hans Mollenkopf, Wilhelm Bertrams, Bernd Schmeck, Matthias Klein, Axel Pagenstecher, Michael Lohoff, Ralf Jacob, Oliver Pabst, Paul William Bland, Maik Luu, Rossana Romero, Britta Siegmund, Krishnaraj Rajalingam, Ulrich Steinhoff
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Research Article Gastroenterology Immunology

Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells

Abstract

The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44+Helios+CD4+ T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10–deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn’s disease revealed significantly reduced frequencies of apoptotic CD4+ T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.

Authors

Alexander Visekruna, Sabrina Hartmann, Yasmina Rodriguez Sillke, Rainer Glauben, Florence Fischer, Hartmann Raifer, Hans Mollenkopf, Wilhelm Bertrams, Bernd Schmeck, Matthias Klein, Axel Pagenstecher, Michael Lohoff, Ralf Jacob, Oliver Pabst, Paul William Bland, Maik Luu, Rossana Romero, Britta Siegmund, Krishnaraj Rajalingam, Ulrich Steinhoff

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Figure 6

Food antigen–activated T cells undergo apoptosis in PPs.

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Food antigen–activated T cells undergo apoptosis in PPs. (A) Expression ...
(A) Expression of CD127 on CD4+ T cells derived from mLNs (black) and PPs (red) of ConvD mice. (B) Flow cytometric analysis of CD127 and Helios in viable Foxp3–CD4+ T cells from PPs of ConvD mice. (C and D) Expression OX40 and Bcl-2 in Helios+Foxp3–CD4+ T cells (red) or Tregs (black) from PPs of Conv mice (n = 4). The filled area shows isotype control staining. (E) Frequencies of annexin V/PI+ CD4+ T cells in spleen, mLNs, siLP, and PPs of ConvD mice. (F) Frequencies of Helios+Foxp3– cells in annexin V+ and annexin V– CD4+ T cells sorted from PPs of ConvD mice (n = 4). (G) Annexin V staining of CD4+CD44hi and CD4+CD44lo CD4+ T cells from PPs of ConvD mice (n = 5). (H) Annexin V+ CD4+ T cells derived from PPs of ConvD and ED mice (n = 5). (I) Immunoblot analysis of sorted CD44hi and CD44lo CD4+ T cells from PPs of ConvD mice for cleavage of PARP and activation of caspases. Data are representative of 2 (F–I) or 3 (A–E) independent experiments. Results are expressed as mean ± SD. Data were analyzed using the Student’s t test; *P < 0.05; ***P < 0.001.