ABSTRACT
Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1-3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid-distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22-producing T cells to orchestrate immune protection in the intestine.
Subject(s)
Citrobacter rodentium , Colon , Epithelial Cells , Intestinal Mucosa , T-Lymphocytes , Animals , Female , Male , Mice , Citrobacter rodentium/immunology , Colon/cytology , Colon/immunology , Colon/microbiology , Enterobacteriaceae Infections/immunology , Enterobacteriaceae Infections/microbiology , Epithelial Cells/immunology , Epithelial Cells/microbiology , Epithelial Cells/metabolism , Histocompatibility Antigens Class II/immunology , Histocompatibility Antigens Class II/metabolism , Interleukin-22/immunology , Interleukin-22/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestinal Mucosa/cytology , Mice, Inbred C3H , Mice, Inbred C57BL , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
In response to infection, naïve CD4+ T cells differentiate into two subpopulations: T follicular helper (TFH) cells, which support B cell antibody production, and non-TFH cells, which enhance innate immune cell functions. Interleukin-2 (IL-2), the major cytokine produced by naïve T cells, plays an important role in the developmental divergence of these populations. However, the relationship between IL-2 production and fate determination remains unclear. Using reporter mice, we found that differential production of IL-2 by naïve CD4+ T cells defined precursors fated for different immune functions. IL-2 producers, which were fated to become TFH cells, delivered IL-2 to nonproducers destined to become non-TFH cells. Because IL-2 production was limited to cells receiving the strongest T cell receptor (TCR) signals, a direct link between TCR-signal strength, IL-2 production, and T cell fate determination has been established.
