scholarly journals The thymus and central tolerance

2001 ◽  
Vol 356 (1409) ◽  
pp. 609-616 ◽  
Author(s):  
Jonathan Sprent ◽  
Hidehiro Kishimoto
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Tolerance Induction ◽  
Cell Receptor ◽  
Immunological Tolerance ◽  
T Cell Differentiation ◽  
Central Tolerance ◽  
Mhc Molecules ◽  
Self Antigens

T–cell differentiation in the thymus generates a peripheral repertoire of mature T cells that mounts strong responses to foreign antigens but is largely unresponsive to self–antigens. This state of specific immunological tolerance to self–components involves both central and peripheral mechanisms. Here we review the process whereby many T cells with potential reactivity for self–antigens are eliminated in the thymus during early T–cell differentiation. This process of central tolerance (negative selection) reflects apoptosis and is a consequence of immature T cells receiving strong intracellular signalling through T–cell receptor (TCR) recognition of peptides bound to major histocompatibility complex (MHC) molecules. Central tolerance occurs mainly in the medullary region of the thymus and depends upon contact with peptide–MHC complexes expressed on bone–marrow–derived antigen–presenting cells (APCs); whether tolerance also occurs in the cortex is still controversial. Tolerance induction requires a combination of TCR ligation and co–stimulatory signals. Co–stimulation reflects interaction between complementary molecules on T cells and APCs and probably involves multiple molecules acting in consort, which may account for why deletion of individual molecules with known or potential co–stimulatory function has little or no effect on central tolerance. The range of self–antigens that induce central tolerance is considerable and, via low–level expression in the thymus, may also include tissue–specific antigens; central tolerance to these latter antigens, however, is likely to be limited to high–affinity T cells, leaving low–affinity cells to escape. Tolerance to alloantigens and the possibility of using central tolerance to promote acceptance of allografts are discussed.

scholarly journals The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+T cells

2020 ◽  
Vol 117 (34) ◽  
pp. 20706-20716 ◽  
Author(s):  
Eliza Mari Kwesi-Maliepaard ◽  
Muhammad Assad Aslam ◽  
Mir Farshid Alemdehy ◽  
Teun van den Brand ◽  
Chelsea McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Receptor ◽  
Histone Methyltransferase ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell ◽  
Developmentally Regulated ◽  
Nucleosome Core ◽  
Normal Differentiation

Cytotoxic T cell differentiation is guided by epigenome adaptations, but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+T cells. T cell-specific ablation ofDot1Lresulted in loss of naïve CD8+T cells and premature differentiation toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8+T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion ofDot1Lin T cells resulted in an impaired immune response. Through our study, DOT1L is emerging as a central player in physiology of CD8+T cells, acting as a barrier to prevent premature differentiation and controlling epigenetic integrity.

scholarly journals Antagonist Peptide Selects Thymocytes Expressing a Class II Major Histocompatibility Complex–restricted T Cell Receptor into the CD8 Lineage

1998 ◽  
Vol 188 (6) ◽  
pp. 1083-1089 ◽  
Author(s):  
Ariane Volkmann ◽  
Thomas Barthlott ◽  
Siegfried Weiss ◽  
Ronald Frank ◽  
Brigitta Stockinger
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
T Cell Differentiation ◽  
Histocompatibility Complex

CD4/CD8 lineage decision is an important event during T cell maturation in the thymus. CD8 T cell differentiation usually requires corecognition of major histocompatibility complex (MHC) class I by the T cell receptor (TCR) and CD8, whereas CD4 T cells differentiate as a consequence of MHC class II recognition by the TCR and CD4. The involvement of specific peptides in the selection of T cells expressing a particular TCR could be demonstrated so far for the CD8 lineage only. We used mice transgenic for an MHC class II-restricted TCR to investigate the role of antagonistic peptides in CD4 T cell differentiation. Interestingly, antagonists blocked the development of CD4+ cells that normally differentiate in thymus organ culture from those mice, and they induced the generation of CD8+ cells in thymus organ culture from mice impaired in CD4+ cell development (invariant chain–deficient mice). These results are in line with recent observations that antagonistic signals direct differentiation into the CD8 lineage, regardless of MHC specificity.

scholarly journals Analysis of Thymocyte Development Reveals That the Gtpase Rhoa Is a Positive Regulator of T Cell Receptor Responses in Vivo

2001 ◽  
Vol 194 (7) ◽  
pp. 903-914 ◽  
Author(s):  
Isabelle Corre ◽  
Manuel Gomez ◽  
Susina Vielkind ◽  
Doreen A. Cantrell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Thymocyte Development

Loss of function of the guanine nucleotide binding protein RhoA blocks pre-T cell differentiation and survival indicating that this GTPase is a critical signaling molecule during early thymocyte development. Previous work has shown that the Rho family GTPase Rac-1 can initiate changes in actin dynamics necessary and sufficient for pre-T cell development. The present data now show that Rac-1 actions in pre-T cells require Rho function but that RhoA cannot substitute for Rac-1 and induce the actin cytoskeletal changes necessary for pre-T cell development. Activation of Rho is thus not sufficient to induce pre-T cell differentiation or survival in the absence of the pre-T cell receptor (TCR). The failure of RhoA activation to impact on pre-TCR–mediated signaling was in marked contrast to its actions on T cell responses mediated by the mature TCR α/β complex. Cells expressing active RhoA were thus hyperresponsive in the context of TCR-induced proliferation in vitro and in vivo showed augmented positive selection of thymocytes expressing defined TCR complexes. This reveals that RhoA function is not only important for pre-T cells but also plays a role in determining the fate of mature T cells.

scholarly journals The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells

2019 ◽  
Author(s):  
Eliza Mari Kwesi-Maliepaard ◽  
Muhammad Assad Aslam ◽  
Mir Farshid Alemdehy ◽  
Teun van den Brand ◽  
Chelsea McLean ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Cell Receptor ◽  
Histone Methyltransferase ◽  
T Cell Differentiation ◽  
Cytotoxic T Cell

AbstractCytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A172-A172
Author(s):  
Guillermo Rangel Rivera ◽  
Guillermo Rangel RIvera ◽  
Connor Dwyer ◽  
Dimitrios Arhontoulis ◽  
Hannah Knochelmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cell Therapy ◽  
Tumor Immunity ◽  
Mitochondrial Function ◽  
T Cell Differentiation ◽  
Tumor Control ◽  
T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

scholarly journals Potential Antiinflammatory Role of Insulin via the Preferential Polarization of Effector T Cells toward a T Helper 2 Phenotype

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 346-353 ◽  
Author(s):  
Alexander Viardot ◽  
Shane T. Grey ◽  
Fabienne Mackay ◽  
Donald Chisholm
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Insulin Receptor ◽  
T Cell Differentiation ◽  
Receptor Expression ◽  
T Helper ◽  
Type Response ◽  
Helper Type

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-γ to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.

scholarly journals Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X

2014 ◽  
Vol 211 (10) ◽  
pp. 1947-1955 ◽  
Author(s):  
Edwina Naik ◽  
Joshua D. Webster ◽  
Jason DeVoss ◽  
Jinfeng Liu ◽  
Rowena Suriben ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tolerance Induction ◽  
Ubiquitin Ligases ◽  
Cell Receptor ◽  
Lymphoproliferative Disease ◽  
Deubiquitinating Enzymes ◽  
Tcr Signaling ◽  
Self Tolerance ◽  
A Cell

The T cell hyperproliferation and autoimmune phenotypes that manifest in mice lacking E3 ubiquitin ligases such as Cbl, ITCH, or GRAIL highlight the importance of ubiquitination for the maintenance of peripheral T cell tolerance. Less is known, however, about the deubiquitinating enzymes that regulate T cell proliferation and effector function. Here, we define a cell intrinsic role for the deubiquitinase Usp9X during proximal TCR signaling. Usp9X-deficient T cells were hypoproliferative, yet mice with T cell–specific Usp9x deletion had elevated numbers of antigen-experienced T cells and expanded PD-1 and OX40-expressing populations consistent with immune hyperactivity. Aged Usp9x KO mice developed lupus-like autoimmunity and lymphoproliferative disease, indicating that ubiquitin ligases and deubiquitinases maintain the delicate balance between effective immunity and self-tolerance.

Sign in / Sign up

Export Citation Format

Share Document