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Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103 + gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter - specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103 + and CD103 - migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103 + migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103 - DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance., Competing Interests: ER, JY, SY, KN, HW, TA, JC, VD, DK, RG, KM, CH No competing interests declared

Self-tolerance of T cells is maintained by a combination of thymic negative selection and suppression by T regulatory cells (Tregs); both processes are driven by recognition of self MHC ligands. Treg function ensures that most T cells remain quiescent as naïve cells, but enables some T cells to proliferate and differentiate into cells with a memory phenotype (MP). In this review, we discuss how Tregs shape this compartmentalization of T cells into subsets of naïve and MP T cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

T cells proliferate vigorously following acute depletion of CD4 + Foxp3 + T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1 -/- hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies., Competing Interests: The authors declare no conflict of interest.

Dysregulation of intestinal microflora is linked to inflammatory disorders associated with compromised immunosuppressive functions of Foxp3 + T regulatory (T reg ) cells. Although mucosa-associated commensal microbiota has been implicated in T reg generation, molecular identities of the "effector" components controlling this process remain largely unknown. Here, we have defined Bifidobacterium bifidum as a potent inducer of Foxp3 + T reg cells with diverse T cell receptor specificity to dietary antigens, commensal bacteria, and B. bifidum itself. Cell surface β-glucan/galactan (CSGG) polysaccharides of B. bifidum were identified as key components responsible for T reg induction. CSGG efficiently recapitulated the activity of whole bacteria and acted via regulatory dendritic cells through a partially Toll-like receptor 2-mediated mechanism. T reg cells induced by B. bifidum or purified CSGG display stable and robust suppressive capacity toward experimental colitis. By identifying CSGG as a functional component of T reg -inducing bacteria, our studies highlight the immunomodulatory potential of CSGG and CSGG-producing microbes., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up- or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C + Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C downregulation was accompanied by proliferation of Ly6C + Treg cells and subsequent change into Ly6C - effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C + Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance.

Dietary antigens are normally rendered nonimmunogenic through a poorly understood "oral tolerance" mechanism that involves immunosuppressive regulatory T (Treg) cells, especially Treg cells induced from conventional T cells in the periphery (pTreg cells). Although orally introducing nominal protein antigens is known to induce such pTreg cells, whether a typical diet induces a population of pTreg cells under normal conditions thus far has been unknown. By using germ-free mice raised and bred on an elemental diet devoid of dietary antigens, we demonstrated that under normal conditions, the vast majority of the small intestinal pTreg cells are induced by dietary antigens from solid foods. Moreover, these pTreg cells have a limited life span, are distinguishable from microbiota-induced pTreg cells, and repress underlying strong immunity to ingested protein antigens., (Copyright © 2016, American Association for the Advancement of Science.)