Summary 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 naïve commensal-reactive transgenic T cells expressing colonic Treg 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 one week post-transfer. Contrary to prior reports, Foxp3+ cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naïve T cell activation. Moreover, Notch2-dependent but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the CNS1 region in Foxp3, nor blockade of TGFβ-receptor signaling, completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, robust, and may be specified by TGFβ-independent signals.

The transcription factors c-Myc and N-Myc encoded by Myc and Mycn, respectively, regulate cellular growth1 and are required for embryonic development2,3. A third paralog, Mycl1, is dispensable for normal embryonic development but its normal biologic function has remained unclear4. To examine the in vivo function of Mycl1, we generated an inactivating Mycl1gfp allele that also reports Mycl1 expression. We found that Mycl1 was selectively expressed in dendritic cells (DCs) of the immune system and controlled by IRF8, and that during DC development, Mycl1 expression was initiated in the common DC progenitor5 (CDP) concurrent with reduction in c-Myc expression. Mature DCs lacked expression of c-Myc and N-Myc, but maintained L-Myc expression even in the presence of inflammatory signals, such as GM-CSF. All DC subsets developed in Mycl1-deficient mice, but several DC subsets, such as migratory CD103+ cDCs in the lung and liver, were significantly reduced at steady state. Importantly, loss of L-Myc by DCs caused a significant decrease in the in vivo T-cell priming during infection by Listeria monocytogenes and vesicular stomatitis virus. The replacement of c-Myc by L-Myc in immature DCs may provide for Myc transcriptional activity in the setting of inflammation that is required for optimal T-cell priming6.

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

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