Strong T cell tolerance in parent----F1 bone marrow chimeras prepared with supralethal irradiation. Evidence for clonal deletion and anergy.

T cell tolerance induction was examined in long-term H-2-heterozygous parent----F1 chimeras prepared with supralethal irradiation (1,300 rad). Although these chimeras appeared to be devoid of host-type APC, the donor T cells developing in the chimeras showed marked tolerance to host-type H-2 determinants. Tolerance to the host appeared to be virtually complete in four assay systems: (a) primary mixed lymphocyte reactions (MLR) of purified lymph node (LN) CD8+ cells (+/- IL-2); (b) primary MLR of CD4+ (CD8-) thymocytes; (c) skin graft rejection; and (d) induction of lethal graft-vs.-host disease by CD4+ cells. Similar tolerance was observed in chimeras given double irradiation. The only assay in which the chimera T cells failed to show near-total tolerance to the host was the primary MLR of post-thymic CD4+ cells. In this assay, LN CD4+ cells regularly gave a significant antihost MLR. The magnitude of this response was two- to fourfold less than the response of normal parental strain CD4+ cells and, in I-E(-)----I-E+ chimeras, was paralleled by approximately 70% deletion of V beta 11+ cells. Since marked tolerance was evident at the level of mature thymocytes, tolerance induction in the chimeras presumably occurred in the thymus itself. The failure to detect host APC in the thymus implies that tolerance reflected contact with thymic epithelial cells (and/or other non-BM-derived cells in the thymus). To account for the residual host reactivity of LN CD4+ cells and the incomplete deletion of V beta 11+ cells, it is suggested that T cell contact with thymic epithelial cells induced clonal deletion of most of the host-reactive T cells but spared a proportion of these cells (possibly low affinity cells). Since these latter cells appeared to be functionally inert in the thymus (in contrast to LN), we suggest that the thymic epithelial cells induced a temporary form of anergy in the remaining host-reactive thymocytes. This anergic state disappeared when the T cells left the thymus and reached LN.

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Proteasome-Generated cis-Spliced Peptides and Their Potential Role in CD8+ T Cell Tolerance

Frontiers in Immunology ◽

10.3389/fimmu.2021.614276 ◽

2021 ◽

Vol 12 ◽

Author(s):

Artem Mansurkhodzhaev ◽

Camila R. R. Barbosa ◽

Michele Mishto ◽

Juliane Liepe

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Response ◽

Thymic Epithelial Cells ◽

Antigenic Peptides ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Peptide Hydrolysis ◽

Clonal Deletion ◽

Infected Cells

The human immune system relies on the capability of CD8+ T cells to patrol body cells, spot infected cells and eliminate them. This cytotoxic response is supposed to be limited to infected cells to avoid killing of healthy cells. To enable this, CD8+ T cells have T Cell Receptors (TCRs) which should discriminate between self and non-self through the recognition of antigenic peptides bound to Human Leukocyte Antigen class I (HLA-I) complexes—i.e., HLA-I immunopeptidomes—of patrolled cells. The majority of these antigenic peptides are produced by proteasomes through either peptide hydrolysis or peptide splicing. Proteasome-generated cis-spliced peptides derive from a given antigen, are immunogenic and frequently presented by HLA-I complexes. Theoretically, they also have a very large sequence variability, which might impinge upon our model of self/non-self discrimination and central and peripheral CD8+ T cell tolerance. Indeed, a large variety of cis-spliced epitopes might enlarge the pool of viral-human zwitter epitopes, i.e., peptides that may be generated with the exact same sequence from both self (human) and non-self (viral) antigens. Antigenic viral-human zwitter peptides may be recognized by CD8+ thymocytes and T cells, induce clonal deletion or other tolerance processes, thereby restraining CD8+ T cell response against viruses. To test this hypothesis, we computed in silico the theoretical frequency of zwitter non-spliced and cis-spliced epitope candidates derived from human proteome (self) and from the proteomes of a large pool of viruses (non-self). We considered their binding affinity to the representative HLA-A*02:01 complex, self-antigen expression in Medullary Thymic Epithelial cells (mTECs) and the relative frequency of non-spliced and cis-spliced peptides in HLA-I immunopeptidomes. Based on the present knowledge of proteasome-catalyzed peptide splicing and neglecting CD8+ TCR degeneracy, our study suggests that, despite their frequency, the portion of the cis-spliced peptides we investigated could only marginally impinge upon the variety of functional CD8+ cytotoxic T cells (CTLs) involved in anti-viral response.

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The Aire family expands

Journal of Experimental Medicine ◽

10.1084/jem.20190246 ◽

2019 ◽

Vol 216 (5) ◽

pp. 1010-1011

Author(s):

Adrian Liston ◽

James Dooley

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Lymph Nodes ◽

Thymic Epithelial Cells ◽

T Cell Tolerance ◽

T Cell Repertoire ◽

Cell Tolerance ◽

Cell Repertoire

T cell tolerance depends upon Aire-expressing cells to purge the T cell repertoire of autoreactive clones. Once thought to be the exclusive domain of thymic epithelial cells, a new study by Yamano et al. (https://doi.org/10.1084/jem.20181430) in this issue of JEM identifies ILC3-like cells in the lymph nodes with similar properties.

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Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion

Blood ◽

10.1182/blood-2011-02-336115 ◽

2011 ◽

Vol 118 (4) ◽

pp. 984-991 ◽

Cited By ~ 29

Author(s):

Sara Morlacchi ◽

Cristiana Soldani ◽

Antonella Viola ◽

Adelaida Sarukhan

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Antigen Expression ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Clonal Deletion ◽

Thymic Epithelium ◽

Self Antigen ◽

Self Antigens

Abstract Multiple mechanisms operate to ensure T-cell tolerance toward self-antigens. Three main processes have been described: clonal deletion, anergy, and deviation to CD4+ regulatory T cells (Tregs) that suppress autoreactive T cells that have escaped the first 2 mechanisms. Although it is accepted that dendritic cells (DCs) and B cells contribute in maintaining T-cell tolerance to self-antigens, their relative contribution and the processes involved under physiologic conditions remain only partially characterized. In this study, we used different transgenic mouse models to obtain chimeras where a neo self-antigen is expressed by thymic epithelium and/or by DCs or B cells. We found that expression of cognate ligand in the thymus enhances antigen-specific FoxP3+ cells independently of whether the self-antigen is expressed on thymic epithelium or only on DCs, but not on B cells. On the contrary, self-antigen expression by B cells was very efficient in inducing FoxP3+ cells in the periphery, whereas self-antigen expression by DC led mainly to deletion and anergy of antigen-specific FoxP3− cells. The results presented in this study underline the role of B cells in Treg induction and may have important implications in clinical protocols aimed at the peripheral expansion of Tregs in patients.

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Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism

Blood ◽

10.1182/blood-2003-10-3697 ◽

2004 ◽

Vol 103 (10) ◽

pp. 3964-3969 ◽

Cited By ~ 65

Author(s):

Ping Lan ◽

Lan Wang ◽

Bintou Diouf ◽

Hiroshi Eguchi ◽

Hui Su ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tolerance Induction ◽

Skin Grafting ◽

Mixed Chimerism ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Human T Cell ◽

Human T Cells ◽

Hematopoietic Chimerism

Abstract Xenotransplantation from pigs could provide a potential solution to the severe shortage of allogeneic donor organs. Because xenogeneic tissues are subject to vigorous immune rejection, tolerance induction is likely to be essential to the success of clinical xenotransplantation. Here we explore the possibility of inducing human T-cell tolerance to porcine xenografts through mixed chimerism. We previously showed that NOD/SCID-Tg mice expressing porcine cytokine transgenes permit the induction of durable porcine hematopoietic chimerism. In this study we achieved human T-cell development in these mice by engrafting human fetal thymus/liver tissues. In porcine hematopoietic chimeras, human thymus grafts were populated with porcine class IIhigh cells in addition to human cells, and human T cells were tolerant of the porcine hematopoietic donor as measured by mixed lymphocyte reaction assay and skin grafting. This study proves the principle that porcine chimerism induces tolerance of xenoreactive human T cells.

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Faculty Opinions recommendation of Autonomous role of medullary thymic epithelial cells in central CD4(+) T cell tolerance.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3539966.3239064 ◽

2010 ◽

Author(s):

Michael Farrar ◽

Kieng Bao Vang

Keyword(s):

T Cell ◽

Epithelial Cells ◽

Cd4 T Cell ◽

Thymic Epithelial Cells ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Medullary Thymic Epithelial Cells

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T cell tolerance studied at the level of antigenic determinants. I. Latent reactivity to lysozyme peptides that lack suppressogenic epitopes can be revealed in lysozyme-tolerant mice.

Journal of Experimental Medicine ◽

10.1084/jem.161.5.897 ◽

1985 ◽

Vol 161 (5) ◽

pp. 897-911 ◽

Cited By ~ 39

Author(s):

A Oki ◽

E Sercarz

Keyword(s):

T Cells ◽

T Cell ◽

Antigenic Determinants ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Clonal Deletion ◽

Amino Terminal ◽

Adult Mice ◽

Novel Approach ◽

Peptide Probes

Whether T cell tolerance represents direct inactivation of antigen-specific T cells via recognition of antigen plus major histocompatibility complex, or via T suppressor (Ts) cells, or a combination of these mechanisms, remains to be clarified. This problem was investigated using a novel approach based on the finding in several systems that T helper/proliferative (Th/Tp) cell-inducing antigenic determinants are dissociable from Ts cell-inducing determinants. Thus, peptide probes containing known sites that stimulate T proliferative activity, as well as peptides from distinct sites assumed to bear Ts-inducing determinants, were used in studying hen (chicken) eggwhite lysozyme (HEL)-tolerant mice. The clear prediction from clonal deletion model is that Th/Tp response potential to short peptides in the tolerant mouse would not exist, while regulatory suppression models predict the coexistence of antigen-reactive cells and antigen-specific regulatory cells that prevent their expression. Adult mice, treated with 2 mg HEL in saline, were tolerant to HEL in complete Freund's adjuvant (CFA). Latent T cell proliferative responses could be revealed to determinants within two HEL peptide probes, which lacked the amino-terminal region of the molecule. This responsiveness suggested two conclusions: first, Ts cells directed against the amino terminus of lysozyme exist in the tolerant genetic responder B10.A; second, these Ts regulate the activity of functional antigen-reactive T cells directed against epitopes elsewhere on the molecule, but only in the presence of the complete molecule, HEL. Examination of neonatally induced tolerance did not reveal any latent responsiveness, supporting the hypothesis that clonal deletion or anergy is the relevant mechanism in this situation. Possible reservations in these explanations of the two tolerant states, plus analysis of the more complex "split tolerance" resulting from 20 mg HEL in saline treatment in adults, are discussed. The approach of dissociation of proliferation-inducing determinants from suppression-inducing determinants clarifies our understanding of the tolerant state and holds promise for more definitive exploration of mechanisms of T cell tolerance.

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CRUCIAL ROLE OF INDIRECT ALLORECOGNITION BY CD4 T CELLS FOR CD8 T CELL TOLERANCE INDUCTION.

Transplantation Journal ◽

10.1097/00007890-200607152-01036 ◽

2006 ◽

Vol 82 (Suppl 2) ◽

pp. 416

Author(s):

&NA;

Keyword(s):

T Cells ◽

T Cell ◽

Crucial Role ◽

Cd4 T Cells ◽

Tolerance Induction ◽

Cd8 T Cell ◽

T Cell Tolerance ◽

Cell Tolerance ◽

Indirect Allorecognition

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Intrathymic elimination of Mlsa-reactive (V beta 6+) cells during neonatal tolerance induction to Mlsa-encoded antigens.

Journal of Experimental Medicine ◽

10.1084/jem.167.6.2005 ◽

1988 ◽

Vol 167 (6) ◽

pp. 2005-2010 ◽

Cited By ~ 86

Author(s):

H R MacDonald ◽

T Pedrazzini ◽

R Schneider ◽

J A Louis ◽

R M Zinkernagel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Genetic Locus ◽

Tolerance Induction ◽

Lymphoid Cells ◽

Strongly Correlated ◽

T Cell Tolerance ◽

Clonal Deletion ◽

Receptor Modulation ◽

Peripheral T Cells

The cellular basis of neonatally induced T cell tolerance has been investigated in a model system in which usage of a particular TCR V beta segment (V beta 6) is strongly correlated with reactivity to antigens encoded by the Mlsa genetic locus. Expression of V beta 6 by peripheral T cells was virtually abolished in BALB/c (H-2d, Mlsb) mice rendered neonatally tolerant to DBA/2 (H-2d, Mlsa) lymphoid cells, whereas control V beta 8-bearing T cells remained at near normal levels. Further analysis revealed that elimination of V beta 6+ T cells occurred in the thymus of neonatally tolerant mice and could not be explained by receptor modulation or T cell chimerism. These data thus support the clonal deletion model of tolerance induction.

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