L-Selectinhi but not the L-selectinlo CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection

Taylor, Patricia A.; Panoskaltsis‐Mortari, Angela; Swedin, Jessica M.; Lucas, Paul A.; Gress, Ronald E.; Levine, Bruce L.; June, Carl H.; Serody, Jonathan S.; Blazar, Bruce R.

doi:10.1182/blood-2004-05-1850

Cited by 321 publications

(273 citation statements)

References 24 publications

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“…To test this premise, we established an acute model of graft-versus-host disease (aGVHD) using irradiated major histocompatibility complex (MHC) haplotype H2 d animals that received allogeneic T cells (MHC haplotype H2 b ) in concert with CD62L low Tregs; alternatively, CD62L low Tregs were transduced with a nondegradative form of KLF2 (16,28) before cotransfer. Consistent with previous reports (29,30), CD62L low Tregs were unable to prevent aGVHD (Fig. 5A) because of inefficient entry into SLOs.…”

Section: Increased Klf2 Expression Within the Treg Compartment Augmentssupporting

confidence: 81%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Tregs are essential for maintaining peripheral tolerance, and thus targeting these cells may aid in the treatment of autoimmunity and cancer by enhancing or reducing suppressive functions, respectively. Before these cells can be harnessed for therapeutic purposes, it is necessary to understand how they maintain tolerance under physiologically relevant conditions. We now report that transcription factor Kruppel-like factor 2 (KLF2) controls naive Treg migration patterns via regulation of homeostatic and inflammatory homing receptors, and that in its absence KLF2-deficient Tregs are unable to migrate efficiently to secondary lymphoid organs (SLOs). Diminished Treg trafficking to SLOs is sufficient to initiate autoimmunity, indicating that SLOs are a primary site for maintaining peripheral tolerance under homeostatic conditions. Disease severity correlates with impaired Treg recruitment to SLOs and, conversely, promotion of Tregs into these tissues can ameliorate autoimmunity. Moreover, stabilizing KLF2 expression within the Treg compartment enhances peripheral tolerance by diverting these suppressive cells from tertiary tissues into SLOs. Taken together, these results demonstrate that peripheral tolerance is enhanced or diminished through modulation of Treg trafficking to SLOs, a process that can be controlled by adjusting KLF2 protein levels.

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Section: Increased Klf2 Expression Within the Treg Compartment Augmentssupporting

confidence: 81%

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Kumar

Rabacal

Volanakis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Whereas CCR7-deficient naive-like Treg fail to recirculate through LN, resulting in an almost complete abolishment of their ability to inhibit the proliferation of naive T cells at this site, effector/memory-like Treg from CCR7 -/-mice display an increased accumulation in inflamed sites, which was accompanied by an enhanced suppression of the inflammatory reaction. CCR7 expression was predominantly observed on naive-like Treg [3,5,6,11,[31][32][33][34] and CCR7-expressing CD62L high CD25 + CD4 + Treg were found to be very efficient in preventing the development of autoimmunity [5] or in suppressing graft-versus-host disease [35,36]. It was suggested that Treg recirculation through LN mediated by CCR7 and CD62L is a prerequisite to suppress priming of autoreactive effector cells.…”

Section: Discussionmentioning

confidence: 99%

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

et al. 2007

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Foxp3 + CD25 + CD4 + Treg play a fundamental role in the maintenance of self tolerance and the control of inflammatory reactions. Previous data demonstrated a division of labor between naive-and effector/memory-like Treg subsets, which is largely based on their lymph node-recirculating and inflammation-seeking migration behavior, respectively. The chemokine receptor CCR7 is expressed on both types of Treg subsets, albeit at different levels. Whether it fulfills similar or distinct roles in these subsets has not been studied so far. We here show that the recirculation of naive-like Treg through LN and, to some extent, the gut is dependent on CCR7. Lack of CCR7 not only prevents recirculation, but also almost completely abolishes the ability of naive-like Treg to control the priming phase of an immune response. In contrast, CCR7 deficiency in effector/memory-like Treg promotes their accumulation in inflamed sites, compatible with a role of CCR7 for exit from the tissue. Local Treg accumulation was accompanied by an enhanced suppression of inflammation. Together, our findings provide conclusive evidence that CCR7 expression on Treg differentially controls in vivo function of the naive-and effector/memory-like subsets.

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“…[48][49][50] For example, CD8 þ TCR À -facilitating cells, derived from BM, induced Treg genes (including Foxp3) 28 days after transplantation. 48 This was observed at the time of full donor engraftment, suggesting that these putative CD4 þ CD25 þ Treg cells were of donor origin.…”

Section: Discussionmentioning

confidence: 99%

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

et al. 2005

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Apoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-bdependent donor CD4 þ CD25 þ T-cell expansion. Such cells have a regulatory phenotype (CD62L high and intracellular CTLA-4 þ ), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover.

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L-Selectinhi but not the L-selectinlo CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection

Abstract: Graft-versus-host disease (GVHD) is

Cited by 321 publications

References 24 publications

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Peripheral tolerance can be modified by altering KLF2-regulated Treg migration

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion

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