Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells

Huehn, Jochen; Siegmund, Kerstin; Lehmann, Joachim; Siewert, Christiane; Haubold, Uta; Feuerer, Markus; Debes, Gudrun F.; Lauber, Jörg; Frey, Oliver; Przybylski, Grzegorz K.; Niesner, Uwe; Rosa, Maurus de la; Schmidt, Christian A.; Bräuer, Rolf; Buer, Jan; Scheffold, Alexander; Hamann, Alf

doi:10.1084/jem.20031562

Cited by 555 publications

(601 citation statements)

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“…Bars display mean AE SD from five individual mice (**p 0.01). We have previously demonstrated that a major fraction of thymus-derived Foxp3 + Treg harbors a naïve-like phenotype, preferentially recirculates through lymphoid organs, and might act predominantly in suppressing the inductive phase of immunes responses occurring in these sites [31,43]. In contrast, effector/memory Treg, characterized by expression of the integrin a E (CD103), display a heterogeneous pattern of tissues-specific homing and chemokine receptors.…”

Section: Migration Behavior Of In Vitro Modulated Tregmentioning

confidence: 99%

“…Cytometric analysis was performed as previously described [31]. Intracellular Foxp3 staining was performed with the PE anti-mouse Foxp3 staining set according to the manufacturers instructions.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…CD25 + CD4 + Treg play a central role in the maintenance of immunological homeostasis and self-tolerance [29]. Treg are by no means homogeneous, but rather can be subdivided into naïve-like subsets, which preferentially recirculate through lymphoid tissues, and effector/memory subsets, which efficiently migrate into peripheral sites and sites of ongoing immune responses [30][31][32][33]. Thus, it is not surprising that Treg display a high HR versatility [31,[34][35][36][37][38][39].…”

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confidence: 99%

“…Treg are by no means homogeneous, but rather can be subdivided into naïve-like subsets, which preferentially recirculate through lymphoid tissues, and effector/memory subsets, which efficiently migrate into peripheral sites and sites of ongoing immune responses [30][31][32][33]. Thus, it is not surprising that Treg display a high HR versatility [31,[34][35][36][37][38][39].A few studies have demonstrated the capacity of Treg to down-regulate established immune reactions [31,[40][41][42], and, therefore, it has been suggested that regulation might act locally in the inflammatory environment. Indeed, we and others have recently demonstrated that expression of certain HR such as selectin ligands and chemokine receptors on Treg subsets critically influences their suppressive capacity in vivo [43][44][45][46], suggesting that appropriate localization is indispensable for Treg function [30].…”

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Induction of organ‐selective CD4⁺ regulatory T cell homing

et al. 2007

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Compelling evidence suggests that Foxp3 + CD25 + CD4 + Treg play a fundamental role in immunoregulation. We have previously demonstrated that Treg have to enter peripheral tissues to suppress ongoing inflammation. However, relatively little is known about how Treg acquire the expression of homing receptors required for tissue-or inflammationspecific migration. Migratory properties of conventional naïve T cells are shaped by the tissue microenvironment and organ-specific dendritic cells during priming. Here, we show that this basic concept also holds true for CD25 + CD4 + Treg: Priming of Treg within peripheral LN led to the expression of selectin ligands, which facilitate migration into inflamed skin, whereas activation within mesenteric LN led to induction of the integrin a 4 b 7 , which is required for migration into mucosal tissues. Furthermore, we could establish in vitro culture systems containing either dendritic cells from mesenteric and peripheral LN, or retinoic acid and IL-12 as polarizing compounds to induce mucosa-and skin-seeking Treg, respectively. Together, our results demonstrate that Treg, similarly to conventional T cells, can be configured with organ-selective homing properties allowing efficient targeting into distinct tissues. IntroductionMigration of T cell subsets to different tissues is determined by the combined expression of adhesion molecules and chemokine receptors (CCR) on the cell surfaces [1][2][3][4]. Among these homing receptors (HR), the integrin a 4 b 7 [5,6] and the chemokine receptor CCR9 [7][8][9] mediate the homing of T cell subsets to GALT such as mesenteric LN (mLN) and Peyer's patches (PP) and to the small intestinal lamina propria and the mucosal epithelium. In contrast, T cell trafficking to the skin is mediated by P-(P-lig) and E-(E-lig) selectin ligands [10,11] as well as .Recently, a number of studies have described that antigen-dependent differentiation of naïve T cells in lymphoid organs leads to the generation of effector T cells exhibiting a capacity to enter peripheral extralymphoid tissues [2]. Effector T cells generated in different lymphoid organs display distinct tissue tropism, which is regulated by an organ-specific induction of adhesion molecules and chemokine receptors during T cell priming [4,[15][16][17][18][19][20][21]. For example, T cells activated in mLN and PP draining the gut acquire high levels of the integrin a 4 b 7 , whereas activation in skin-draining peripheral LN (pLN) results in the upregulation of selectin ligands such as P-lig. Tissuespecific DC have been shown in a number of in vitro and in vivo studies to be involved in the instruction of naïve T cells [4,[17][18][19][20][22][23][24] reported that GALT DC were capable of converting metabolites of dietary vitamin A into retinoic acid (RA), which in turn induced T cell expression of a 4 b 7 and CCR9, leading to the generation of gut-tropic T cells. However, the factors, which are involved in the generation of skin-specific T cell homing in vivo, are largely unknown, although important ...

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Section: Migration Behavior Of In Vitro Modulated Tregmentioning

confidence: 99%

Section: Flow Cytometrymentioning

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Induction of organ‐selective CD4⁺ regulatory T cell homing

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“…1A). These effector/ memory-like Treg (e/mTreg) are characterized by the expression of the integrin a E (CD103)b 7 [29]. The increase of these e/mTreg was first detectable in MLN in the early acute phase at day 6 post infection (p.i.)…”

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Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

et al. 2009

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Here, we show that Treg limit intestinal pathology during nematode infection and that they control the onset and magnitude of the anti-parasitic Th Th2 response. Using mice expressing the diptheria toxin receptor under the control of the foxp3 locus, we removed Foxp3 1 Treg during the early phase of infection with Heligmosomoides polygyrus bakeri. Depletion of Treg in infected animals did not affect adult worm burden, but led to increased pathology at the site of infection. Infected, depleted mice displayed higher frequencies of activated CD4 1 T cells and increased levels of the Th2 cytokines IL-4 and IL-13. The stronger parasite-specific Th2 response was accompanied by higher levels of IL-10. Only a moderate change in Th1 (IFN-c) reactivity was detected in worm-infected, Treg-depleted mice. Furthermore, we detected an accelerated onset of parasite-specific Th2 and IL-10 responses in the transient absence of Foxp3 1 Treg. However, adult worm burdens were not affected by the increased Th2-reactivity in Treg-depleted mice. Hence, our data show that Treg restrict the onset and strength of Th2 responses during intestinal worm infection, while increasing primary Th2 responses does not necessarily lead to killing of larvae or accelerated expulsion of adult worms.Key words: Foxp3 . Nematode . Pathology . Th2 response . Treg IntroductionParasitic worms are the most potent inducers of highly polarized Th cell type 2 (Th2) responses. Helminth infections tend to be long lasting and are often associated with insufficient immunity to re-infection [1,2]. Chronic infections favor immunosuppression, the so-called modulated Th2-response, associated with poor parasite-specific reactivity alongside with the strong production of anti-inflammatory cytokines, such as . This helminth-induced immunosuppression may spill over to bystander antigens [3], downmodulate reactivity against other pathogens [4] and impair vaccination efficacy [5]. However, such effects can be beneficial by downregulating inflammatory reactions to allergens and inflammatory disorders of the intestinal tract. Studies in animal models showed that helminths can suppress airway hyperreactivity and colitis [6][7][8] and nematodes have been used to efficiently treat human inflammatory bowel disease in clinical trials [9,10]. 3066In animal models, the beneficial effects of nematode infections on inflammatory disorders were associated with the presence of Treg populations [6,11,12]. However, it is not yet clear whether such Treg suppress anti-parasite immune reactivity and thus contribute to survival and well-being of the worms, or whether they predominantly dampen immunopathology. Several studies investigated the role of Treg in infections with helminths or other parasites and yielded in diverging conclusions (reviewed in [1] and [13]). There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].In a previous study ...

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CTLA‐4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice

Kolar¹,

Knieke²,

Hegel³

et al. 2008

Arthritis & Rheumatism

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Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells

Cited by 555 publications

References 56 publications

Induction of organ‐selective CD4⁺ regulatory T cell homing

Induction of organ‐selective CD4⁺ regulatory T cell homing

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

CTLA‐4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice

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Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells

Cited by 555 publications

References 56 publications

Induction of organ‐selective CD4+ regulatory T cell homing

Induction of organ‐selective CD4+ regulatory T cell homing

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

CTLA‐4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in mice

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Induction of organ‐selective CD4⁺ regulatory T cell homing

Induction of organ‐selective CD4⁺ regulatory T cell homing

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells