Lymph Node Occupancy Is Required for the Peripheral Development of Alloantigen-Specific Foxp3+ Regulatory T Cells

Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2005; 174(11):6993-7005. DOI: 10.4049/jimmunol.174.11.6993
Source: PubMed


We previously demonstrated that L-selectin (CD62L)-dependent T cell homing to lymph nodes (LN) is required for tolerance induction to alloantigen. To explore the mechanisms of this observation, we analyzed the development and distribution of regulatory T cells (Treg), which play an important protective role against allograft rejection in transplantation tolerance. Alloantigen-specific tolerance was induced using either anti-CD2 plus anti-CD3 mAbs, or anti-CD40L mAbs plus donor-specific transfusion, in fully mismatched (BALB/c donor, C57BL/6 recipient) vascularized cardiac allografts. An expansion of CD4(+)CD25(+)CD62L(high) T cells was observed specifically within the LN of tolerant animals, but not in other anatomic sites or under nontolerizing conditions. These cells exhibited a substantial up-regulation of Foxp3 expression as measured by real-time PCR and by fluorescent immunohistochemistry, and possessed alloantigen-specific suppressor activity. Neither LN nor other lymphoid cells expressed the regulatory phenotype if recipients were treated with anti-CD62L mAbs, which both prevented LN homing and caused early allograft rejection. However, administration of FTY720, a sphingosine 1-phosphate receptor modulator that induces CD62L-independent T cell accumulation in the LNs, restored CD4(+)CD25(+) Treg in the LNs along with graft survival. These data suggest that alloantigen-specific Foxp3(+)CD4(+)CD25(+) Treg develop and are required within the LNs during tolerization, and provide compelling evidence that distinct lymphoid compartments play critical roles in transplantation tolerance.

Download full-text


Available from: Sergio Lira, Aug 13, 2014
  • Source
    • "Matsuoka et al. [37] found that CD4+ lymphopenia was a critical factor in Treg cell homeostasis, and that prolonged imbalance of Treg cell homeostasis resulted in a loss of tolerance and significant clinical disease manifestations. Moreover, some studies had shown that homing of Treg cells into the draining lymph nodes was required for the suppressive function of these cells [38,39]. Therefore, the specific suppressive function of topical 0.5% FTY720 on corneal transplantation can be explained by significantly increasing the percentage of Treg cells in the cervical lymph nodes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the effects of topical FTY720 and cyclosporin A (CsA) on allogeneic corneal transplantation in mice. A total of 75 BALB/c mice received corneal grafts from C57BL/6 donors. Recipients were treated with 0.1%, 0.3%, or 0.5% FTY720 ophthalmic gel or 1% CsA eye-drops after the graft (controls received no treatment). The number of cluster of differentiation (CD)4+ T cells and CD4+CD25+forkhead box P3 (Foxp3)+ regulatory (Treg) cell phenotypes were measured by flow cytometry. Cytokine mRNA expression in corneal grafts was analyzed by real-time quantitative PCR. CD4 + T cells and cytokines in corneal samples were identified by immunohistochemical staining. Corneal graft survival was prolonged by treatment with topical 0.5% FTY720 (mean survival time [MST], 24.1±1.6 days) or 1% CsA eye-drops (MST 25.0±1.9 days) compared with controls (MST, 13.4±0.5 days; n=9, both p<0.01). Topical 0.5% FTY720 treatment significantly increased the percentages of CD4 + T (p<0.05) and Treg cells (p<0.01; n=5) in the cervical lymph nodes compared with controls. Transforming growth factor-β1 (TGF-β1) mRNA transcription in corneal grafts after topical 0.5% FTY720 increased (p<0.05, n=3), while interleukin-2 (IL-2) and interferon-γ (IFN-γ) mRNA expression in corneal grafts treated with 1% CsA decreased (p<0.01, p<0.05, respectively). These cytokine results were paralleled by similar immunohistochemical staining. Topical 0.5% FTY720 and 1% CsA treatment reduced the infiltration of CD4+ Tcells in the grafts. Topical 0.5% FTY720 and 1% CsA can effectively prolong allogeneic corneal graft survival in mice. Treatment with topical 0.5% FTY720 increases the percentage of CD4+ T cells and the percentage of Treg cells in cervical lymph nodes. The 0.5% FTY720 increased TGF-β1 mRNA expression and decreases infiltration of CD4+ T cells in corneal grafts, while topical 1% CsA down-regulated the expression of IL-2 and IFN-γ.
    Molecular vision 03/2012; 18:624-33. · 1.99 Impact Factor
  • Source
    • "Furthermore, the presence of MBP-specific [69] or PLP-specific [75] Treg cells was associated with prevention of EAE. However, the self-reactivity of the Treg repertoire has been challenged by reports of Treg cells recognizing foreign antigens from bacteria [38, 80], fungi [81], the protozoan parasite Leishmania major [82, 83], allergens [30] and alloantigens [84, 85]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CD4(+) T cells are commonly divided into regulatory T (Treg) cells and conventional T helper (Th) cells. Th cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. Treg cells are defined as CD4(+) T cells in charge of suppressing potentially deleterious activities of Th cells. This review briefly summarizes the current knowledge in the Treg field and defines some key questions that remain to be answered. Suggested functions for Treg cells include: prevention of autoimmune diseases by maintaining self-tolerance; suppression of allergy, asthma and pathogen-induced immunopathology; feto-maternal tolerance; and oral tolerance. Identification of Treg cells remains problematic, because accumulating evidence suggests that all the presently-used Treg markers (CD25, CTLA-4, GITR, LAG-3, CD127 and Foxp3) represent general T-cell activation markers, rather than being truly Treg-specific. Treg-cell activation is antigen-specific, which implies that suppressive activities of Treg cells are antigen-dependent. It has been proposed that Treg cells would be self-reactive, but extensive TCR repertoire analysis suggests that self-reactivity may be the exception rather than the rule. The classification of Treg cells as a separate lineage remains controversial because the ability to suppress is not an exclusive Treg property. Suppressive activities attributed to Treg cells may in reality, at least in some experimental settings, be exerted by conventional Th cell subsets, such as Th1, Th2, Th17 and T follicular (Tfh) cells. Recent reports have also demonstrated that Foxp3(+) Treg cells may differentiate in vivo into conventional effector Th cells, with or without concomitant downregulation of Foxp3.
    Scandinavian Journal of Immunology 10/2009; 70(4):326-36. DOI:10.1111/j.1365-3083.2009.02308.x · 1.74 Impact Factor
  • Source
    • "+ regulatory cells controlling allograft transplantation tolerance (Ochando et al., 2005) and in the lymphoid organs of HIV-infected individuals (Andersson et al., 2005). The demonstration of robust mucosal immune responses but no regulatory activity to influenza virus even in children implies that the Treg identified in our studies are not entirely non-specific and that their induction may not be universal to immunity against organisms of the nasopharynx. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neisseria meningitidis is commonly carried asymptomatically in the upper respiratory tract and only occasionally invades the bloodstream and meninges to cause disease. Naturally acquired immunity appears protective but the nature of the cellular immune response within the mucosa is uncertain. We show that following in vitro stimulation with N. meningitidis serogroup B (MenB) antigens, approximately 66% of the dividing mucosal CD4(+)CD45RO(+) memory population express the Th1-associated IL18-R while the remainder express CRTH2, a Th2-associated marker. The pro-inflammatory bias of this anti-MenB response is not evident in blood, demonstrating compartmentalization at the induction site; and occurs in the presence or absence of lipopolysacharide indicating that these responses are already fully committed. Depletion of CD25(+) cells reveals suppression of the effector CD4(+) T cell response restricted to the mucosa and most marked in children (i.e. those at greatest risk of disease). Mucosal T-regulatory cell (Treg) activity is partially overcome by blocking the human glucocorticoid-induced TNF receptor (GITR) and is not seen following stimulation with antigens from another mucosal pathogen, influenza virus. Pro-inflammatory, antimeningococcal T cell responses may limit invasive disease at the mucosa but Treg induction while reducing immunopathological damage, may also restrict the effectiveness of the protective response, particularly in children.
    Cellular Microbiology 05/2007; 9(4):1050-61. DOI:10.1111/j.1462-5822.2006.00851.x · 4.92 Impact Factor
Show more