scholarly journals The role of peripheral T–cell deletion in transplantation tolerance

2001 ◽  
Vol 356 (1409) ◽  
pp. 617-623 ◽  
Author(s):  
Andrew D. Wells ◽  
Xian–Chang Li ◽  
Terry B. Strom ◽  
Laurence A. Turka
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Tolerance ◽  
Treatment Modalities ◽  
Transplantation Tolerance ◽  
Potential Contribution ◽  
Clonal Deletion ◽  
Self Tolerance ◽  
Clonal Anergy

The apoptotic deletion of thymocytes that express self–reactive antigen receptors is the basis of central (thymic) self–tolerance. However, it is clear that some autoreactive T cells escape deletion in the thymus and exist as mature lymphocytes in the periphery. Therefore, peripheral mechanisms of tolerance are also crucial, and failure of these peripheral mechanisms leads to autoimmunity. Clonal deletion, clonal anergy and immunoregulation and/or suppression have been suggested as mechanisms by which ‘inappropriate’ T–lymphocyte responses may be controlled in the periphery. Peripheral clonal deletion, which involves the apoptotic elimination of lymphocytes, is critical for T–cell homeostasis during normal immune responses, and is recognized as an important process by which self–tolerance is maintained. Transplantation of foreign tissue into an adult host represents a special case of ‘inappropriate’ T–cell reactivity that is subject to the same central and peripheral tolerance mechanisms that control reactivity against self. In this case, the unusually high frequency of naive T cells able to recognize and respond against non–self–allogeneic major histocompatibility complex (MHC) antigens leads to an exceptionally large pool of pathogenic effector lymphocytes that must be controlled if graft rejection is to be avoided. A great deal of effort has been directed toward understanding the role of clonal anergy and/or active immunoregulation in the induction of peripheral transplantation tolerance but, until recently, relatively little progress had been made towards defining the potential contribution of clonal deletion. Here, we outline recent data that define a clear requirement for deletion in the induction of peripheral transplantation tolerance across MHC barriers, and discuss the potential implications of these results in the context of current treatment modalities used in the clinical transplantation setting.

Double Negative T Cells Influence TCR VB Variablity to Induce Allotolerance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 759-759
Author(s):  
Zachariah A. McIver ◽  
Marcin Wlodarski ◽  
Jennifer Powers ◽  
Christine O’Keefe ◽  
Tao Jin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Peripheral Tolerance ◽  
Double Negative ◽  
Clonal Deletion ◽  
Tcr Repertoire ◽  
Double Negative T Cells

Abstract Immune alloresponsiveness following allogeneic HSCT is influenced by the dynamics of immune reconstitution and development of allotolerance. In general, tolerance is induced by thymic clonal deletion (central) and apoptosis or suppression of alloresponsive lymphocytes by regulatory T cells in the periphery. We have recently demonstrated that the size of the TCR repertoire within the CD4 and CD8 compartments can be assessed using VB spectrum by flow cytometry, and expansions/losses of individual TCR VB families can be used as a surrogate marker of TCR variability. (Exp. Hem.32: 1010–1022; Br. J. Haematol.129:411–419). Additionally, regulatory T cells can also impact the clonal contractions and expansions within the TCR VB repertoire. Various types of regulatory T cells have been described including CD4+CD25+, CD8+, NK T−cells, and CD3+CD4/CD8− double negative T cells (DN Tregs). In our current study we investigated the role of DN Tregs on the restoration of immune repertoire diversity. We hypothesized that alloresponsiveness clinically detected as a manifestation of GvHD may be associated with oligoclonal T−cell expansions, and in this context decreased numbers of regulatory T cells suggest deficient tolerizing function by regulatory T cells including DN Tregs. Here we studied a cohort of 60 HSCT recipients (AML, CML, CLL, NHL, AA, and PV), of which 25 patients received matched unrelated donor grafts and 35 received matched sibling donor grafts. Blood was sampled between 2003–2006 at monthly intervals after HSCT, and flow cytometry for TCR repertoire in CD4 and CD8 cells as well as the numbers of DN cells were recorded. Additionally, separate samples were collected for measurement of chimerism and were included in analysis when donor lymphoid chimerism was > 60%. A subset analysis was performed based on the presence/absence of GvHD. For the 27/60 (45%) patients with episodes of GvHD, results were obtained at the time of diagnosis of GvHD (grade > 2), while for patients in whom notable GvHD was not captured, the steady−state values at corresponding times were used for analysis. For all patients serial evaluations were available. For the purpose of this study, significant VB expansions/contractions were defined as +/− 2 standard deviation over the average VB family size. Using Cox proportional hazards analysis to identify univariate risk factors for GVHD, CD8 VB TCR contractions > 14 VB families (58.3% contraction of entire CD4 VB repertoire) constituted a strong indicator for increased risk (HR=7.61, p=0.011). This observation is consistent with the fact that oligoclonality of alloreactive T cell clones is frequently accompanied by a significant contraction/loss of remaining VB families and may herald heightened alloresponsiveness as a manifestation of GvHD. Estimation for correlation by Pearson’s correlation coefficient also demonstrated that percentage of DN cells strongly correlated with a normalization of CD4 VB TCR repertoire (lower number of expansions; N=57, R= −0.51, p=0.027), supporting our hypothesis that DN cells participate in peripheral tolerance and suppress proliferative, alloresponsive CD4 clones. In summary, our results further characterize TCR variability post HSCT and define the role of DN cells in the induction of allotolerance.

scholarly journals Regulatory Role of CD4+ T Cells in Myocarditis

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Daria Vdovenko ◽  
Urs Eriksson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Young Patients ◽  
Peripheral Tolerance ◽  
T Cell Subsets ◽  
High Plasticity ◽  
Clonal Deletion ◽  
Effector T Cell

Myocarditis is an important cause of heart failure in young patients. Autoreactive, most often, infection-triggered CD4+ T cells were confirmed to be critical for myocarditis induction. Due to a defect in clonal deletion of heart-reactive CD4+ T cells in the thymus of mice and humans, significant numbers of heart-specific autoreactive CD4+ T cells circulate in the blood. Normally, regulatory T cells maintain peripheral tolerance and prevent spontaneous myocarditis development. In the presence of tissue damage and innate immune activation, however, activated self-antigen-loaded dendritic cells promote CD4+ effector T cell expansion and myocarditis. So far, a direct pathogenic role has been described for both activated Th17 and Th1 effector CD4+ T cell subsets, though Th1 effector T cell-derived interferon-gamma was shown to limit myocarditis severity and prevent transition to inflammatory dilated cardiomyopathy. Interestingly, recent observations point out that various CD4+ T cell subsets demonstrate high plasticity in maintaining immune homeostasis and modulating disease phenotypes in myocarditis. These subsets include Th1 and Th17 effector cells and regulatory T cells, despite the fact that there are still sparse and controversial data on the specific role of FOXP3-expressing Treg in myocarditis. Understanding the specific roles of these T cell populations at different stages of the disease progression might provide a key for the development of successful therapeutic strategies.

scholarly journals Induction of autoreactive B cells allows priming of autoreactive T cells.

1991 ◽  
Vol 173 (6) ◽  
pp. 1433-1439 ◽  
Author(s):  
R H Lin ◽  
M J Mamula ◽  
J A Hardin ◽  
C A Janeway
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cytochrome C ◽  
Autoantibody Production ◽  
Autoreactive T Cells ◽  
Human Cytochrome ◽  
Self Tolerance ◽  
Human Cytochrome C

A novel mechanism for breaking T cell self tolerance is described. B cells induced to make autoantibody by immunization of mice with the non-self protein human cytochrome c can present the self protein mouse cytochrome c to autoreactive T cells in immunogenic form. This mechanism of breaking T cell self tolerance could account for the role of foreign antigens in breaking not only B cell but also T cell self tolerance, leading to sustained autoantibody production in the absence of the foreign antigen.

scholarly journals Essential role of CCL21 in establishment of central self-tolerance in T cells

2017 ◽  
Vol 214 (7) ◽  
pp. 1925-1935 ◽  
Author(s):  
Mina Kozai ◽  
Yuki Kubo ◽  
Tomoya Katakai ◽  
Hiroyuki Kondo ◽  
Hiroshi Kiyonari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Essential Role ◽  
Functional Inequality ◽  
Cell Accumulation ◽  
Self Tolerance ◽  
Thymic Medulla ◽  
Deficient Mice

The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.

Ex vivo–expanded DCs induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin grafts

Blood ◽  
2011 ◽  
Vol 117 (9) ◽  
pp. 2640-2648 ◽  
Author(s):  
Tomoyoshi Yamano ◽  
Sho Watanabe ◽  
Hiroyuki Hasegawa ◽  
Toshihiro Suzuki ◽  
Ryo Abe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Peripheral Tolerance ◽  
Skin Grafts ◽  
Major Histocompatibility ◽  
Clonal Deletion ◽  
Activated T Cells ◽  
Donor Skin ◽  
Major Histocompatibility Complexes

Abstract Dendritic cells (DCs) are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide–major histocompatibility complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T-cell development, induction of T-cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs, obtained from bone marrow cultured with either Flt3L (FLDCs) or granulocyte-macrophage colony-stimulating factor (GMDCs), could induce allospecific central and peripheral tolerance after IV injection; B cells were used as a control. The results showed that only FLDCs reached the thymus after injection and that these cells induced both central and peripheral tolerance to donor major histocompatibility complexes. For central tolerance, injection of FLDCs induced antigen-specific clonal deletion of both CD8 and CD4 single-positive thymocytes. For peripheral tolerance, injection of FLDCs induced donor-specific T-cell unresponsiveness and prolonged survival of donor-derived skin grafts. Tolerance induction by adoptive transfer of FLDCs could be a useful approach for promoting graft acceptance after organ transplantation.

scholarly journals Dendritic Cells: Cellular Mediators for Immunological Tolerance

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Chun Yuen J. Chung ◽  
Dirk Ysebaert ◽  
Zwi N. Berneman ◽  
Nathalie Cools
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Autoimmune Diseases ◽  
Inflammatory Diseases ◽  
Immunological Tolerance ◽  
Immunosuppressive Drugs ◽  
Peripheral Tolerance ◽  
Regulatory Function ◽  
Clonal Deletion

In general, immunological tolerance is acquired upon treatment with non-specific immunosuppressive drugs. This indiscriminate immunosuppression of the patient often causes serious side-effects, such as opportunistic infectious diseases. Therefore, the need for antigen-specific modulation of pathogenic immune responses is of crucial importance in the treatment of inflammatory diseases. In this perspective, dendritic cells (DCs) can have an important immune-regulatory function, besides their notorious antigen-presenting capacity. DCs appear to be essential for both central and peripheral tolerance. In the thymus, DCs are involved in clonal deletion of autoreactive immature T cells by presenting self-antigens. Additionally, tolerance is achieved by their interactions with T cells in the periphery and subsequent induction of T cell anergy, T cell deletion, and induction of regulatory T cells (Treg). Various studies have described, modulation of DC characteristics with the purpose to induce antigen-specific tolerance in autoimmune diseases, graft-versus-host-disease (GVHD), and transplantations. Promising results in animal models have prompted researchers to initiate first-in-men clinical trials. The purpose of current review is to provide an overview of the role of DCs in the immunopathogenesis of autoimmunity, as well as recent concepts of dendritic cell-based therapeutic opportunities in autoimmune diseases.

scholarly journals CCR4 promotes medullary entry and thymocyte–dendritic cell interactions required for central tolerance

2015 ◽  
Vol 212 (11) ◽  
pp. 1947-1965 ◽  
Author(s):  
Zicheng Hu ◽  
Jessica N. Lancaster ◽  
Chayanit Sasiponganan ◽  
Lauren I.R. Ehrlich
Keyword(s):  
T Cells ◽  
T Cell ◽  
Positive Selection ◽  
Time Lapse ◽  
Cell Receptor ◽  
Peripheral Tolerance ◽  
Central Tolerance ◽  
Self Tolerance ◽  
Thymic Medulla ◽  
Antigen Presenting

Autoimmunity results from a breakdown in central or peripheral tolerance. To establish central tolerance, developing T cells must enter the thymic medulla, where they scan antigen-presenting cells (APCs) displaying a diverse array of autoantigens. If a thymocyte is activated by a self-antigen, the cell undergoes either deletion or diversion into the regulatory T cell (T reg) lineage, thus maintaining self-tolerance. Mechanisms promoting thymocyte medullary entry and interactions with APCs are incompletely understood. CCR4 is poised to contribute to central tolerance due to its expression by post-positive selection thymocytes, and expression of its ligands by medullary thymic dendritic cells (DCs). Here, we use two-photon time-lapse microscopy to demonstrate that CCR4 promotes medullary entry of the earliest post-positive selection thymocytes, as well as efficient interactions between medullary thymocytes and DCs. In keeping with the contribution of thymic DCs to central tolerance, CCR4 is involved in regulating negative selection of polyclonal and T cell receptor (TCR) transgenic thymocytes. In the absence of CCR4, autoreactive T cells accumulate in secondary lymphoid organs and autoimmunity ensues. These studies reveal a previously unappreciated role for CCR4 in the establishment of central tolerance.

Role of regulatory T-cells in autoimmunity

2009 ◽  
Vol 116 (8) ◽  
pp. 639-649 ◽  
Author(s):  
Richard J. Mellanby ◽  
David C. Thomas ◽  
Jonathan Lamb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Subset ◽  
Treg Cells ◽  
Self Tolerance

There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.

scholarly journals Transplantation Tolerance Induced in Humans at the Fetal or the Neonatal Stage

2011 ◽  
Vol 2011 ◽  
pp. 1-4 ◽  
Author(s):  
Jean-Louis Touraine ◽  
Kamel Sanhadji
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
Conditioning Regimen ◽  
Host Cells ◽  
Positive Interactions ◽  
Transplantation Tolerance ◽  
Cell Repertoire ◽  
Clonal Deletion

Patients transplanted with HLA-mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens. Engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity, especially T-cell differentiation. The chimeric patients have donor-derived T lymphocytes which progressively demonstrate positive interactions with other host cells. They also can be shown to be tolerant toward both host and donor antigens. The latter tolerance relies upon clonal deletion from the T-cell repertoire, and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells. The former tolerance does not imply clonal deletion of T-cells with host reactivity. Numerous T-cells recognizing the allogeneic, host-type antigens are identified in these patients, but these cells are anergized, following interaction with epithelial cells of the host thymus. Induction of transplantation tolerance at the fetal stage requires minimal engraftment only; in the future it will be possible to further amplify the clinical benefit, using additional cell transplants after birth.

Relationship Between Galectin-10 Expression and Severity of Celiac Disease Abolished in the Presence of Gammadelta-Positive T-Cell Clonal Expansion

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4922-4922
Author(s):  
Maria Paola Simula ◽  
Valli De Re ◽  
Mariangela De Zorzi ◽  
Vincenzo Canzonieri ◽  
Michele Spina ◽  
...  
Keyword(s):  
T Cells ◽  
Celiac Disease ◽  
T Cell ◽  
Chronic Antigenic Stimulation ◽  
Parallel Increase ◽  
Self Tolerance ◽  
Genescan Analysis ◽  
High Production ◽  
Cell Proliferations

Abstract Celiac disease (CD) patients are prone to develop T-cell lymphoma throughout a progressive accumulation of aberrant, clonal gd+ T-cells. It is supposed that high production of pro-inflammatory cytokines, and chronic antigenic stimulation, due to gluten ingestion, plays a key role in inducing inflammation, resistance to apoptosis and the emergence of these T-clones. Regulatory T-cells maintain immunological self-tolerance by active suppression of auto aggressive T-cells. Among them, Tr1 subset plays a role in the suppression of naïve and memory T-cells. The role of Tr1 in human diseases is not well understood, even because there are no specific markers able to identify these cells, however recently, Galectin-10 has been proposed as a marker for functional Tr1. To better understand pathogenetic mechanisms associated with CD and clonal T-cell proliferations we investigated galectin-10 expression from gut epithelium by 2D-DIGE approaches. Patients were selected and grouped for histological inflammatory degree and for gd+T pattern defined by g-TCR genescan analysis. Groups consisted of 7 individuals with Marsh-0 (4/7 oligoclonal), 3 with a Marsh-1 or -2 (3/3 polyclonal) and 5 with Marsh-3 (2/5 clonal gd+T). Control consisted of 4 individuals with excluded CD. We found, a parallel increase in galectin-10 levels and Marsh index in individuals with polyclonal gd+T cells (p=0.0092), while reduced levels were evidenced from patients with clonal gd+T cells and Marsh-3 (p=0.017). We assume that galectin-10 up-expression is induce to an attempt to extinguish inflammation. If these clones are those more susceptible to malignant progression reserve further exploration.

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