scholarly journals Negative T cell selection on non-random peptides promotes robust self-nonself discrimination

2018 ◽  
Author(s):  
Inge M N Wortel ◽  
Can Keşmir ◽  
Rob J De Boer ◽  
Judith N Mandl ◽  
Johannes Textor
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Negative Selection ◽  
Computational Models ◽  
Adaptive Immune System ◽  
Cross Reactivity ◽  
Cell Repertoire ◽  
T Cell Selection ◽  
Self Peptides

Our adaptive immune system has the remarkable ability to distinguish previously unseen foreign peptides from harmless self. This self-foreign discrimination was long thought to arise from the silencing of self-reactive T cells during negative selection in the thymus, but recent data show that negative selection is far from complete. Here we ask how a repertoire containing many self-reactive T cells can nevertheless discriminate self from foreign. We address this question using realistic-scale computational models of the T cell repertoire. Our models show that moderate T cell cross-reactivity automatically skews the post-selection repertoire towards peptides that differ systematically from self. But even when no systematic differences between self and foreign exist, discrimination remains possible if the peptides presented in the thymus are chosen in a way that minimizes the co-occurrence of similar, redundant self peptides. Thus, our model predicts that negative selection on a well-chosen subset of self peptides biases the resulting repertoire towards better detection of both self-similar and -dissimilar pathogens. This effect would allow the immune system to "learn self by example", an ability shared with cognitive systems.

scholarly journals Is T Cell Negative Selection a Learning Algorithm?

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 690 ◽  
Author(s):  
Inge M. N. Wortel ◽  
Can Keşmir ◽  
Rob J. de Boer ◽  
Judith N. Mandl ◽  
Johannes Textor
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Negative Selection ◽  
Learning Algorithm ◽  
Selection Process ◽  
Cross Reactivity ◽  
Cell Repertoire ◽  
Thymic Medulla ◽  
Self Peptides

Our immune system can destroy most cells in our body, an ability that needs to be tightly controlled. To prevent autoimmunity, the thymic medulla exposes developing T cells to normal “self” peptides and prevents any responders from entering the bloodstream. However, a substantial number of self-reactive T cells nevertheless reaches the periphery, implying that T cells do not encounter all self peptides during this negative selection process. It is unclear if T cells can still discriminate foreign peptides from self peptides they haven’t encountered during negative selection. We use an “artificial immune system”—a machine learning model of the T cell repertoire—to investigate how negative selection could alter the recognition of self peptides that are absent from the thymus. Our model reveals a surprising new role for T cell cross-reactivity in this context: moderate T cell cross-reactivity should skew the post-selection repertoire towards peptides that differ systematically from self. Moreover, even some self-like foreign peptides can be distinguished provided that the peptides presented in the thymus are not too similar to each other. Thus, our model predicts that negative selection on a well-chosen subset of self peptides would generate a repertoire that tolerates even “unseen” self peptides better than foreign peptides. This effect would resemble a “generalization” process as it is found in learning systems. We discuss potential experimental approaches to test our theory.

scholarly journals Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Josephine F. Reijneveld ◽  
Mira Holzheimer ◽  
David C. Young ◽  
Kattya Lopez ◽  
Sara Suliman ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Immune System ◽  
T Cell ◽  
Cross Reactivity ◽  
Lipid Binding ◽  
Human Immune System ◽  
Human T Cell ◽  
Human T Cells ◽  
Pure Compounds

AbstractThe cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT1, DAT2, and DAT3. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT1- and DAT2-treated CD1b tetramers were recognized by T cells, but DAT3-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT2 tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT3 by human T cells, DAT3, but not DAT1 or DAT2, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.

In Vivo T-Lymphocyte Tolerance in the Absence of Thymic Clonal Deletion Mediated by Hematopoietic Cells

Blood ◽  
1999 ◽  
Vol 93 (11) ◽  
pp. 3856-3862 ◽  
Author(s):  
Joost P.M. van Meerwijk ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
Apoptotic Cell ◽  
Hematopoietic Cells ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clonal Deletion

Abstract Thymic negative selection renders the developing T-cell repertoire tolerant to self-major histocompatability complex (MHC)/peptide ligands. The major mechanism of induction of self-tolerance is thought to be thymic clonal deletion, ie, the induction of apoptotic cell death in thymocytes expressing a self-reactive T-cell receptor. Consistent with this hypothesis, in mice deficient in thymic clonal deletion mediated by cells of hematopoietic origin, a twofold to threefold increased generation of mature thymocytes has been observed. Here we describe the analysis of the specificity of T lymphocytes developing in the absence of clonal deletion mediated by hematopoietic cells. In vitro, targets expressing syngeneic MHC were readily lysed by activated CD8+ T cells from deletion-deficient mice. However, proliferative responses of T cells from these mice on activation with syngeneic antigen presenting cells were rather poor. In vivo, deletion-deficient T cells were incapable of induction of lethal graft-versus-host disease in syngeneic hosts. These data indicate that in the absence of thymic deletion mediated by hematopoietic cells functional T-cell tolerance can be induced by nonhematopoietic cells in the thymus. Moreover, our results emphasize the redundancy in thymic negative selection mechanisms.

scholarly journals T Cell Regulation as a Side Effect of Homeostasis and Competition

2003 ◽  
Vol 197 (4) ◽  
pp. 451-460 ◽  
Author(s):  
Thomas Barthlott ◽  
George Kassiotis ◽  
Brigitta Stockinger
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Side Effect ◽  
Regulatory Function ◽  
T Cell Repertoire ◽  
Shared Resources ◽  
Cell Repertoire ◽  
Intact Immune System ◽  
Homeostatic Expansion

We have previously hypothesized that maintaining a balanced peripheral immune system may not be the sole responsibility of a specialized subset of T cells dedicated to immune regulation, but also a side effect of normal competition for shared resources within an intact immune system. Here we show that regulatory activity is correlated with high homeostatic expansion potential, reflecting the avidity for self-peptide:MHC complexes. Monoclonal transgenic T cells with high homeostatic expansion potential and lacking characteristics previously associated with regulatory function were able to regulate wasting disease induced by transfer of a small number of naive CD45RBhi CD4 T cells into lymphopenic hosts. Self-regulatory function is also found in the naive polyclonal T cell repertoire depleted of CD25+ T cells. T cells capable of preventing immune pathology, like the transgenic T cells, express higher than average levels of CD5, an indicator of avidity for self:MHC peptide complexes. We therefore propose that dysregulated expansion of potentially pathogenic T cells in a lymphopenic environment can be prevented by members of the naive T cell repertoire, irrespective of their specificity, as a side effect of their response to homeostatic and antigenic stimulation.

The Croonian Lecture, 1992. The key role of the thymus in the body’s defence strategies

1992 ◽  
Vol 337 (1279) ◽  
pp. 105-124 ◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Division Of Labour ◽  
T Cell Subsets ◽  
Lymphoid Tissues ◽  
Cell Repertoire ◽  
Long Time ◽  
T Cell Selection

For centuries the thymus has remained a mysterious organ with largely unknown functions. The first demonstration of its crucial role in the development of the immune system was reported in 1961, when it was found that mice thymectomized at birth had poorly developed lymphoid tissues, impaired immune reactivities, and an inordinate susceptibility to develop infections. Although thymus lymphocytes were for a long time deemed immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating to give rise to a progeny of cells which did not secrete antibody (T cells), but which had a remarkable ability to induce bone marrow cells (B cells) to become antibody formers. This was the first unequivocal demonstration of a major division of labour among mammalian lymphocytes. Tremendous progress in our understanding of the function of the thymus and of the T cells derived from it followed. Distinct T cell subsets were characterized and shown to have an essential role in initiating and regulating a variety of immune responses. The ontogenetic events which occurred during their differentiation were mapped, and this allowed studies of the selection of the T cell repertoire. The major histocompatibility complex and associated peptides were shown to govern T cell selection and antigen activation, and the antigen-specific T cell receptor and the genes which code for it were characterized. Future studies should allow some insight into how to activate T cells more effectively for vaccination purposes, and how to switch them off to prevent autoimmune reactions and to induce tolerance to transplanted tissues.

scholarly journals T-cell populations specifically depleted of alloreactive potential cannot be induced to lyse H-2-different virus-infected target cells.

1978 ◽  
Vol 148 (1) ◽  
pp. 128-135 ◽  
Author(s):  
J R Bennink ◽  
P C Doherty
Keyword(s):  
T Cells ◽  
T Cell ◽  
Negative Selection ◽  
Target Cells ◽  
Type B ◽  
Cell Repertoire ◽  
Infected Cells ◽  
Selection For ◽  
Viral Components ◽  
Lymphocyte Populations

Mouse lymphocyte populations of one parental H-2 type (A) were specificially depleted of alloreactive potential by filtration through irradiated A X B F1 recipients, and thoracic duct cells were then stimulated with virus in an A X B F1 environment. Experiments using T cells that had previously been exposed to influenza virus in the context of A established that cross-priming for recognition of viral components expressed on H-2-different (B) target cells does not occur. Furthermore, immunologically naive T cells stimulated with vaccinia virus, subsequent to negative selection for reactivity to B, could not be shown to interact with virus-infected cells of type B. Either there is no significant T-cell repertoire for recognition of virus associated with an H-2 determinant not encountered during ontogeny, or such T cells are also alloreactive and are removed during filtration.

scholarly journals Immune system derived from homeostatic proliferation generates normal CD8 T-cell memory but altered repertoires and diminished heterologous immune responses

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 680-689 ◽  
Author(s):  
Sue-Jane Lin ◽  
Alex T. Chen ◽  
Raymond M. Welsh
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Homeostatic Proliferation ◽  
Memory Cells ◽  
Cell Repertoire ◽  
Cell Responses

AbstractThe host responds to lymphopenic environments by acute homeostatic proliferation of T lymphocytes, which acquire phenotypes similar to memory cells. Using T-cell knockout (KO) mice adoptively reconstituted with splenocytes from immunologically naive mice, we examined the immune responses of an immune system derived from homeostatically proliferating (HP) T cells. HP cells mounted relatively normal acute CD8 T-cell responses to lymphocytic choriomeningitis virus (LCMV), but with altered T-cell receptor (TCR) repertoires, and they became functional memory cells capable of recall responses. Although homeostatic proliferation does not normally fully restore T-cell numbers, the CD8+ T-cell pool was completely restored in T-cell KO mice after LCMV infection. CD4 T-cell responses were lower and not fully restored but seemed sufficient to allow for complete differentiation of CD8 memory T cells. The LCMV-immune HP mouse had an immune repertoire heavily biased with LCMV epitope-specific T cells with oligoclonal expansions. LCMV-immune HP mice had reduced cross-reactive and non–cross-reactive CD8 T-cell responses when challenged with a T cell–cross-reactive virus. Thus, whereas an HP immune system is capable of mounting relatively normal acute and memory CD8 T-cell responses, the narrowing of the T-cell repertoire may reduce immune responses to subsequently encountered pathogens.

scholarly journals Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus.

1995 ◽  
Vol 182 (5) ◽  
pp. 1481-1491 ◽  
Author(s):  
E V Fedoseyeva ◽  
R C Tam ◽  
P L Orr ◽  
M R Garovoy ◽  
G Benichou
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Tolerance Induction ◽  
Class Ii ◽  
The Self ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Mhc Class Ii Molecules ◽  
Self Peptides

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.

scholarly journals Differential major histocompatibility complex-related activation of idiotypic suppressor T cells. Suppressor T cells cross-reactive to two distantly related lysozymes are not induced by one of them.

1980 ◽  
Vol 152 (3) ◽  
pp. 521-531 ◽  
Author(s):  
L Adorini ◽  
M A Harvey ◽  
D Rozycka-Jackson ◽  
A Miller ◽  
E E Sercarz
Keyword(s):  
T Cells ◽  
T Cell ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Cross Reactivity ◽  
Suppressor T Cells ◽  
Cell Repertoire ◽  
Helper Cells

B10 (H-2b) mice are genetic nonresponders to hen egg-white lysozyme (HEL) and the distantly related human lysozyme (HUL). However, anti-HEL or anti-HUL primary antibody responses in vivo or in vitro can be obtained in B10 mice by immunization with the appropriate lysozyme coupled to erythrocytes. T cells able to suppress either anti-lysozyme plaque-forming cells (PFC) response are induced in B10 mice after immunization with HEL-complete Freund's adjuvant (CFA) or HUL-CFA. This cross-reactivity of HEL and HUL in the induction and the expression of suppressive activity is in marked contrast to their very low cross-reactivity at the PFC level. These results suggest that either HEL or HUL can stimulate a suppressor T cell which recognizes a particular epitope present on both lysozymes. Suppressor cells induced by HEL or HUL bear the same predominant idiotype found on the majority of anti-HEL antibodies, and on the small proportion of anti-HUL antibodies cross-reactive with HEL. B10.Q (H-2q) mice are responders in vivo to HEL-CFA, but not to HUL-CFA. In contrast to B10, HEL-CFA priming in B10.Q micr induces helper cells whereas HUL-CFA priming induces suppressor cells. These suppressor cells are cross-reactive with HEL and are fully able to suppress HEL-specific helper cells. The presence of HEL-specific suppressor cell precursors in B10.Q mice which are not activated by HEL, seems to implicate differential choice by the antigen presenting system as a basis for Ir gene control, rather than the absence of a regulatory cell type from the T cell repertoire.

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