Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery

• DOI: 10.1016/j.celrep.2016.08.092
• Publication Date: 2016-09-28T10:47:16Z
• Authors: Katherine Nutsch; Jiani N. Chai; Teresa L. Ai; Emilie Russler-Ge...; Taylor Feehley; Cathryn R. Nagler; Chyi-Song Hsieh
• Keywords: 0301 basic medicine; QH301-705.5; Colon; pTreg; peripheral regulatory T cells; Gene Expression; Mice, Transgenic; T-Lymphocytes, Regulatory; CNS1 Foxp3; Immunophenotyping; TGFβ; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Immune Tolerance; Animals; Mesentery; Receptor, Notch2; Biology (General); Symbiosis; Antigens, Bacterial; commensal microbiota; Forkhead Transcription Factors; Dendritic Cells; Adoptive Transfer; Gastrointestinal Microbiome; Notch2-dependent dendritic cells; Lymph Nodes; T-Lymphocytes, Cytotoxic

Commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal tolerance. However, little is known about this process. Here, we use the transfer of naive commensal-reactive transgenic T cells expressing colonic Treg T cell receptors (TCRs) to study peripheral Treg (pTreg) cell development in normal hosts. We found that T cells were activated primarily in the distal mesenteric lymph node. Treg cell induction was rapid, generating >40% Foxp3(+) cells 1 week after transfer. Contrary to prior reports, Foxp3(+) cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naive T cell activation. Moreover, Notch2-dependent, but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the conserved nucleotide sequence 1 (CNS1) region in Foxp3 nor blockade of TGF-β (transforming growth factor-β)-receptor signaling completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, is robust, and may be specified by TGF-β-independent signals.