scholarly journals HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression1

2018 ◽  
Author(s):  
Jennifer Schloss ◽  
Riyasat Ali ◽  
Jeremy J. Racine ◽  
Harold D. Chapman ◽  
David V. Serreze ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Mouse Model ◽  
Disease Onset ◽  
Cell Subset ◽  
Class I ◽  
Class I Mhc ◽  
Insulin Expression

ABSTRACTType 1 diabetes (T1D) is characterized by T cell-mediated destruction of the insulin-producing βcells of the pancreatic islets. Among the loci associated with T1D risk, those most predisposing are found in the MHC region. HLA-B*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset. To establish an NOD mouse model for the study of HLA-B*39:06, we expressed it in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells, support lymphocytic infiltration of the islets, and confer T1D susceptibility. Because reduced thymic insulin expression is associated with increased T1D risk in patients, we incorporated this in our model as well, finding that HLA-B*39:06-transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared to littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vβ family usage, indicating that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, we propose that it allows the thymic escape of insulin-reactive HLA-B*39:06-restricted T cells which participate in β cell destruction. We also found that in mice expressing either HLA-B*39:06 or HLA-A*02:01 in the absence of murine class I MHC, HLA transgene identity alters TCR Vβ usage, which may contribute to varying diabetogenic CD8 T cell repertoires in the presence of different HLA class I alleles.

scholarly journals Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients

2012 ◽  
Vol 209 (1) ◽  
pp. 51-60 ◽  
Author(s):  
Ken T. Coppieters ◽  
Francesco Dotta ◽  
Natalie Amirian ◽  
Peter D. Campbell ◽  
Thomas W.H. Kay ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Direct Proof ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Class I ◽  
Β Cell ◽  
Cell Reactivity

A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2–expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.

scholarly journals IPEX as a Result of Mutations in FOXP3

2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Hans J. J. van der Vliet ◽  
Edward E. Nieuwenhuis
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Subset ◽  
Clinical Implications ◽  
Immune Homeostasis ◽  
Immunoregulatory Cells ◽  
Autoimmune Phenomena

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutations in theFOXP3gene that result in the defective development ofCD4+CD25+regulatory T cells which constitute an important T cell subset involved in immune homeostasis and protection against autoimmunity. Their deficiency is the hallmark of IPEX and leads to severe autoimmune phenomena including autoimmune enteropathy, dermatitis, thyroiditis, and type 1 diabetes, frequently resulting in death within the first 2 years of life. Apart from its clinical implications, IPEX illustrates the importance of immunoregulatory cells such asCD4+CD25+regulatory T cells.

scholarly journals Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?

Diabetologia ◽  
2020 ◽  
Vol 64 (1) ◽  
pp. 15-25 ◽  
Author(s):  
Alexia Carré ◽  
Sarah J. Richardson ◽  
Etienne Larger ◽  
Roberto Mallone
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cells ◽  
Disease Onset ◽  
Strong Support ◽  
Islet Autoimmunity ◽  
Relative Role ◽  
Age Related

AbstractAvailable evidence provides arguments both for and against a primary pathogenic role for T cells in human type 1 diabetes. Genetic susceptibility linked to HLA Class II lends strong support. Histopathology documents HLA Class I hyperexpression and islet infiltrates dominated by CD8+ T cells. While both hallmarks are near absent in autoantibody-positive donors, the variable insulitis and residual beta cells of recent-onset donors suggests the existence of a younger-onset endotype with more aggressive autoimmunity and an older-onset endotype with more vulnerable beta cells. Functional arguments from ex vivo and in vitro human studies and in vivo ‘humanised’ mouse models are instead neutral or against a T cell role. Clinical support is provided by the appearance of islet autoantibodies before disease onset. The faster C-peptide loss and superior benefits of immunotherapies in individuals with younger-onset type 1 diabetes reinforce the view of age-related endotypes. Clarifying the relative role of T cells will require technical advances in the identification of their target antigens, in their detection and phenotyping in the blood and pancreas, and in the study of the T cell/beta cell crosstalk. Critical steps toward this goal include the understanding of the link with environmental triggers, the description of T cell changes along the natural history of disease, and their relationship with age and the ‘benign’ islet autoimmunity of healthy individuals.

scholarly journals Characterization of two distinct primary T cell populations that secrete interleukin 2 upon recognition of class I or class II major histocompatibility antigens.

1986 ◽  
Vol 163 (3) ◽  
pp. 603-619 ◽  
Author(s):  
T Mizuochi ◽  
S Ono ◽  
T R Malek ◽  
A Singer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Response ◽  
Cell Subset ◽  
Class Ii ◽  
Class I ◽  
Cell Populations ◽  
Class I Mhc ◽  
T Cell Subset ◽  
Class Ii Mhc

This study has characterized the primary T cell subpopulations that secrete IL-2 in response to recognition of either class I or class II MHC encoded determinants. The addition to culture of anti-IL-2-R mAb inhibited the consumption of IL-2 by activated lymphocytes during the response period, permitting a much more accurate assessment of the amount of IL-2 produced in the response cultures. Using this response system, we found that primary T cell populations contain two IL-2-secreting T cell subsets that express reciprocal phenotypes and different MHC recognition specificities: an L3T4+, Lyt-2- T cell subset responsive to both class I and class II MHC alloantigens, and an L3T4-Lyt-2+ T cell subset responsive only to class I MHC alloantigens. The L3T4+ T cell subset expressed a broad functional response repertoire in that L3T4+ T cells were triggered to secrete IL-2 upon recognition of unmodified self-Ia determinants, allogeneic Ia determinants, and class I alloantigens presented by self-Ia determinants. The activation of L3T4+ IL-2-secreting T cells, even those responsive to class I MHC alloantigens, could be blocked completely by anti-Ia mAbs, confirming that the L3T4+ T cell subset was in fact class II restricted. In contrast, the Lvt-2+ T cell subset expressed a narrow functional response repertoire in that they were triggered to secrete IL-2 only in response to allogeneic class I MHC determinants, and were not triggered to secrete IL-2 even in response to TNP-modified self-MHC determinants. The specificity of Lyt-2+ IL-2-secreting T cells for class I MHC allodeterminants was confirmed by the observations that: (a) their activation could be blocked completely by anti-class I mAbs, (b) they could be triggered by Ia- cell lines which expressed class I MHC alloantigens and possessed accessory function, and (c) they responded to class I MHC alloantigens but failed to respond to class II MHC alloantigens, even in the presence of exogenously added second signals that circumvented the requirement for alloantigen-bearing accessory cells. Finally, the frequency of primary Lyt-2+ T cells that secreted IL-2 in response to class I (Kbm1) MHC alloantigens was shown to be only minimally lower than that of L3T4+ T cells that secreted IL-2 in response to class II (I-Abm12) MHC alloantigens.(ABSTRACT TRUNCATED AT 400 WORDS)

A unique T cell subset described as CD4loCD40+ T cells (TCD40) in human type 1 diabetes

2007 ◽  
Vol 124 (2) ◽  
pp. 138-148 ◽  
Author(s):  
Dan M. Waid ◽  
Rebecca J. Wagner ◽  
Amy Putnam ◽  
Gisela M. Vaitaitis ◽  
Nathan D. Pennock ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Subset ◽  
T Cell Subset ◽  
Human Type ◽  
Human Type 1 Diabetes

scholarly journals Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurie G. Landry ◽  
Amanda M. Anderson ◽  
Holger A. Russ ◽  
Liping Yu ◽  
Sally C. Kent ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd4 T Cells ◽  
Pancreatic Beta Cells ◽  
Hot Spot ◽  
Cell Receptor ◽  
Organ Donors ◽  
Hla Dq

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

scholarly journals T Cell Activity Correlates with Oligomeric Peptide-Major Histocompatibility Complex Binding on T Cell Surface

2001 ◽  
Vol 276 (50) ◽  
pp. 47320-47328 ◽  
Author(s):  
Jennifer Buslepp ◽  
Rui Zhao ◽  
Debora Donnini ◽  
Douglas Loftus ◽  
Mohamed Saad ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Clone ◽  
Cell Activity ◽  
Class I ◽  
Antigenic Peptides ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
T Cell Clone

Recognition of virally infected cells by CD8+T cells requires differentiation between self and nonself peptide-class I major histocompatibility complexes (pMHC). Recognition of foreign pMHC by host T cells is a major factor in the rejection of transplanted organs from the same species (allotransplant) or different species (xenotransplant). AHIII12.2 is a murine T cell clone that recognizes the xenogeneic (human) class I MHC HLA-A2.1 molecule (A2) and the syngeneic murine class I MHC H-2 Dbmolecule (Db). Recognition of both A2 and Dbare peptide-dependent, and the sequences of the peptides recognized have been determined. Alterations in the antigenic peptides bound to A2 cause large changes in AHIII12.2 T cell responsiveness. Crystal structures of three representative peptides (agonist, null, and antagonist) bound to A2 partially explain the changes in AHIII12.2 responsiveness. Using class I pMHC octamers, a strong correlation is seen between T cell activity and the affinity of pMHC complexes for the T cell receptor. However, contrary to previous studies, we see similar half-lives for the pMHC multimers bound to the AHIII12.2 cell surface.

scholarly journals TLR3 essentially promotes protective class I–restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 967-977 ◽  
Author(s):  
Agostinho Carvalho ◽  
Antonella De Luca ◽  
Silvia Bozza ◽  
Cristina Cunha ◽  
Carmen D'Angelo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aspergillus Fumigatus ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Class I ◽  
Class I Mhc ◽  
Cell Responses ◽  
Memory Cd8 T Cell

Abstract Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8+ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8+ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.

scholarly journals Self–class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels

2009 ◽  
Vol 206 (10) ◽  
pp. 2253-2269 ◽  
Author(s):  
Kensuke Takada ◽  
Stephen C. Jameson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Survival ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Class I ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
T Cell Survival ◽  
And Function

Previous studies have suggested that naive CD8 T cells require self-peptide–major histocompatability complex (MHC) complexes for maintenance. However, interpretation of such studies is complicated because of the involvement of lymphopenic animals, as lymphopenia drastically alters naive T cell homeostasis and function. In this study, we explored naive CD8 T cell survival and function in nonlymphopenic conditions by using bone marrow chimeric donors and hosts in which class I MHC expression is absent or limited to radiosensitive versus radioresistant cells. We found that long-term survival of naive CD8 T cells (but not CD4 T cells) was impaired in the absence of class I MHC. However, distinct from this effect, class I MHC deprivation also enhanced naive CD8 T cell responsiveness to low-affinity (but not high-affinity) peptide–MHC ligands. We found that this improved sensitivity was a consequence of up-regulated CD8 levels, which was mediated through a transcriptional mechanism. Hence, our data suggest that, in a nonlymphopenic setting, self-class I MHC molecules support CD8 T cell survival, but that these interactions also attenuate naive T cell sensitivity by dynamic tuning of CD8 levels.

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