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Results for “thymic selection”

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PubMed2002

CD6: expression during development, apoptosis and selection of human and mouse thymocytes.

CD6, a 130-kDa surface glycoprotein, is expressed primarily on cells of T lineage. A co-stimulatory role for CD6 in mature T cells has been shown, but the function of CD6 during thymocyte development is unknown. Since CD6 ligands are expressed on thymic epithelium, their interactions with CD6 could be important in thymic selection. In this report we show that CD6 is developmentally regulated in human and mouse thymocytes, and further demonstrate that increase in the level of CD6 expression correlates with expression of the selection marker CD69. We also show that activation via CD2 induces CD6 expression on mature human thymocytes and on a subset of immature human thymocytes that are resistant to apoptosis. In human and mouse thymocytes that express heterogeneous TCR, CD6 increases occur as double-positive thymocytes are selected to a single-positive stage. In contrast, in thymocytes from TCR transgenic mice, CD6 is barely increased following selection, suggesting that as functional avidity increases, requirements for CD6-dependent co-stimulation decrease. Taken together, these results indicate that during thymic development CD6-dependent signals may contribute both to thymocyte survival, and to the overall functional avidity of selection in both man and mouse.

Animals↗
PubMed1996

Thymic stromal cells can support B cell differentiation from intrathymic precursors.

T lineage cells are the predominant intrathymic population, but low numbers of thymic B cells are also present in the thymus. Recent studies describing the contribution of thymic B cells to the shaping of the T cell repertoire have raised the question as to whether they are produced intrathymically and the potential role of the thymic stroma in this process. During the course of studies aimed at testing the B cell developmental potential of CD4-CD8-CD3/TCR- triple-negative thymocytes present in a newly developed, stromal cell-dependent, long term culture system, the ability of selected thymic stromal cells to support distinct stages of B cell development was revealed. Some thymic stromal cell lines maintained cells with B cell developmental potential but could not support their differentiation, while other selected lines efficiently supported the development of surface IgM-expressing cells from triple-negative precursors. Thymic surface IgM+ B cells were generated most efficiently from thymocytes harvested from relatively young mice. Taken together, the results of this study demonstrate that the thymic microenvironment exhibits a functional heterogeneity in its ability to support different stages of B cell development.

Aging↗
PubMed2006

Role of TCR specificity in CD4+ CD25+ regulatory T-cell selection.

CD4+ CD25+ regulatory T cells play a crucial role in preventing autoimmune disease and can also modulate immune responses in settings such as transplantation and infection. We have developed a transgenic mouse system in which the role that T-cell receptor (TCR) specificity for self-peptides plays in the formation of CD4+ CD25+ regulatory T cells can be examined. We have shown that interactions with a single self-peptide can induce thymocytes bearing an autoreactive TCR to undergo selection to become CD4+ CD25+ regulatory T cells and that thymocytes bearing TCRs with low affinity for the selecting peptide do not appear to undergo selection into this pathway. In addition, thymocytes with identical specificity for the selecting self-peptide can undergo overt deletion versus abundant selection to become CD4+ CD25+ regulatory T cells in response to variations in expression of the selecting peptide in different lineages of transgenic mice. Finally, we have shown that CD4+ CD25+ T cells proliferate in response to their selecting self-peptide in the periphery, but these cells do not proliferate in response to lymphopenia in the absence of the selecting self-peptide. These studies are determining how the specificity of the TCR for self-peptides directs the thymic selection and peripheral expansion of CD4+ CD25+ regulatory T cells.

Animals↗
PubMed2000

Altered selection of CD4+ T cells by class II MHC bound with dominant and low abundance self-peptides.

We have investigated the development of CD4(+) T cells in mice expressing low levels of transgenic class II MHC molecules (A(b)) preoccupied with covalent peptide (Ep), which in the presence of invariant chain (Ii) is extensively cleaved and replaced with self-derived peptides. In these mice, the transgenic A(b) molecules, bound with predominant peptide (Ep) and with multiple self-peptides, selected more CD4(+) T cells than A(b)/self-peptide complexes expressed in wild-type mice. The enhanced outcome of thymic selection was a result of impaired negative selection, rather than more efficient positive selection by an overall lowered abundance of self-derived A(b)/peptide complexes. Peripheral CD4(+) T cells in the A(b)EpIi(+) mice had memory phenotype, often followed by polyclonal activation of B cells. The A(b)EpIi(+) mice preserved their good health and had a normal life span despite the profound number of activated CD4(+) T cells and B cells in peripheral lymphoid organs, moderate hypergammaglobulinemia, and deposited complexes in the kidneys. We propose that CD4(+) T cells positively selected due to low avidity for high abundant A(b)Ep complex avoid negative selection on A(b) molecules loaded with low abundant peptides and become self-reactive in the peripheral lymphoid organs.

Animals↗
PubMed2003

Homology between an alloantigen and a self MHC allele calibrates the avidity of the alloreactive T cell repertoire independent of TCR affinity.

The self-restricted T cell repertoire exhibits a high frequency of alloreactivity. Because these alloreactive T cells are derived from the pool of cells selected on several different self MHC alleles, it is unknown how development of the alloantigenic repertoire is influenced by homology between a self MHC allele and an alloantigen. To address this, we used the 2C transgenic TCR that is selected by K(b), is alloreactive for L(d), and cross-reacts with L(q). L(q) is highly homologous to L(d) and binds several of the same peptide ligands, including p2Ca, the peptide recognized by 2C. We find that L(d)/p2Ca is a high avidity agonist ligand, whereas L(q)/p2Ca is a low avidity agonist ligand for 2C T cells. When mice transgenic for the 2C TCR are bred to L(q)-expressing mice, 2C(+) T cells develop; however, they express lower levels of either the 2C TCR or CD8 and require a higher L(d)/p2Ca ligand density to be activated than 2C(+) T cells selected by K(b). Furthermore, the 2C T cells selected in the presence of L(q) fail to detect L(q)/p2Ca complexes even at high ligand density. Thus, despite possessing the identical TCR, there is a functional avidity difference between 2C(+) T cells selected in the presence of L(q) vs K(b). These data provide evidence that homology between the selecting ligand and an alloantigen can influence the avidity of the T cell repertoire for the alloantigen, and suggest that thymic selection can fine tune T cell avidity independent of intrinsic TCR affinity.

Alleles↗
PubMed1994

TCR selection and allelic exclusion in RAG transgenic mice that exhibit abnormal T cell localization in lymph nodes and lymphatics.

RAG-1 and RAG-2 are developmentally regulated genes that are essential for V(D)J recombination and lymphocyte development. Expression of RAG-1 and RAG-2 by thymocytes is normally limited to cells that have not completed selection. We have previously documented that persistent expression of the recombinase activating genes (RAG) in transgenic mice results in aberrant thymic development, altered lymphatic microanatomy, and a profound immunodeficiency. Here we further document the pathologic changes found in TG.RAG-1,2 mice and examine the role of TCR recombination and positive and negative thymic selection, as well as allelic exclusion, in the etiology of the phenotype. We find that neither selection nor TCR allelic exclusion can be overcome by transgenic expression RAG-1 and RAG-2 under the control of an lck promoter.

Alleles↗
PubMed1998

Degree of TCR internalization and Ca2+ flux correlates with thymocyte selection.

Recent evidence suggests that TCR down-regulation directly reflects the number of TCRs that have engaged MHC/peptide ligand complexes. Here, we examined the influence of defined peptides on thymic selection based on their ability to induce differential TCR internalization. Our results demonstrate that there is a direct correlation: peptides that induce strong TCR down-regulation are most efficient at mediating negative selection, whereas peptides that induce suboptimal TCR internalization are more efficient at triggering positive selection. As a consequence of suboptimal TCR internalization, a proportion of TCR complexes that remain on the cell surface may be able to relay continual signals required for survival and differentiation. In addition, we show that the magnitude of Ca2+ influx set by these peptides reflects the hierarchy of TCR down-regulation and correlates with positive vs negative selection of transgenic thymocytes. Together, our data suggest that T cell selection is mediated by differing intensities of the same TCR-mediated signal, rather than by distinct signals.

Animals↗
PubMed1999

Greatly reduced efficiency of both positive and negative selection of thymocytes in CD45 tyrosine phosphatase-deficient mice.

The T cell repertoire is shaped by positive and negative selection of thymocytes. TCR-mediated signals that determine these selection processes are only partly understood. The CD45 tyrosine phosphatase has been shown to be important for signal transduction through the TCR, but there has been disagreement about whether CD45 is a positive or negative regulator of TCR signaling. Using CD45-deficient mice expressing transgenic TCR, we show that in the absence of CD45 there is a large increase in the thresholds of TCR stimulation required for both positive and negative selection. Our results conclusively demonstrate that in double-positive thymocytes CD45 is a positive regulator of the TCR signals that drive thymic selection events.

Animals↗
PubMed2006

Cross-positive selection of thymocytes expressing a single TCR by multiple major histocompatibility complex molecules of both classes: implications for CD4+ versus CD8+ lineage commitment.

This study has investigated the cross-reactivity upon thymic selection of thymocytes expressing transgenic TCR derived from a murine CD8+ CTL clone. The Idhigh+ cells in this transgenic mouse had been previously shown to mature through positive selection by class I MHC, Dq or Lq molecule. By investigating on various strains, we found that the transgenic TCR cross-reacts with three different MHCs, resulting in positive or negative selection. Interestingly, in the TCR-transgenic mice of H-2q background, mature Idhigh+ T cells appeared among both CD4+ and CD8+ subsets in periphery, even in the absence of RAG-2 gene. When examined on beta2-microglobulin-/- background, CD4+, but not CD8+, Idhigh+ T cells developed, suggesting that maturation of CD8+ and CD4+ Idhigh+ cells was MHC class I (Dq/Lq) and class II (I-Aq) dependent, respectively. These results indicated that this TCR-transgenic mouse of H-2q background contains both classes of selecting MHC ligands for the transgenic TCR simultaneously. Further genetic analyses altering the gene dosage and combinations of selecting MHCs suggested novel asymmetric effects of class I and class II MHC on the positive selection of thymocytes. Implications of these observations in CD4+/CD8+ lineage commitment are discussed.

Animals↗
PubMed1997

A shift from negative to positive selection of autoreactive T cells by the reduced level of TCR signal in TCR-transgenic CD3 zeta-deficient mice.

T cell selection is thought to be determined through the interaction between TCR and Ag/MHC. However, the contribution of the level of TCR signal to thymic selection remains unclear. To address this issue, we analyzed T cell selection of male Ag (HY)-specific TCR transgenic (HYTg) mice crossed with CD3 zeta-deficient (zeta KO) mice (HYTg/zeta KO), which have impaired signaling through TCR. In male HYTg/zeta KO mice, the number of thymocytes was comparable to that in normal mice, and almost all the peripheral T cells were HY specific, although these positively selected cells were anergic to male Ag. From these observations, the decrease in TCR signaling by CD3 zeta deficiency resulted in both the avoidance of negative selection and the acquisition of positive selection of autoreactive T cells in male HYTg/zeta KO mice. There was a shift of T cell selection from positive to no selection of HY-specific T cells in female HYTg/zeta KO mice also. Collectively, these findings suggest that the level of TCR signal directly regulates T cell selection; furthermore, the findings have integrated the models of T cell selection into a concept based on the quantity of TCR signal.

Animals↗
PubMed2002

Spatial relation between major histocompatibility complex-restricted antigen receptor-bearing thymocytes and subtypes of thymic epithelial cells.

R73, a monoclonal antibody that recognizes a rat T cell surface antigen of TCR(alphabeta), was used to identify thymocytes that express major histocompatibility complex-restricted antigen receptors, and to define the spatial relation between these receptor-bearing thymocytes and individual thymic cortical and medullary epithelial subtypes by ultrastructural immunohistochemistry. We show that in both the cortex and medulla 1) the thymocytes that reacted with R73 antibodies exhibited three staining patterns: cytoplasmic-only staining, simultaneous cytoplasmic and surface membrane staining, and surface membrane-only staining; 2) the subcapsular/perivascular epithelial cells (ECs) were usually associated with thymocytes expressing perinuclear staining only; and 3) the surface membrane areas of thymocytes that expressed antigen receptors made contact with pale and intermediate ECs, but not with dark cells. These results suggest that thymic selection of major histocompatibility complex restriction and/or tolerance may occur by interaction of the receptors on maturing thymocytes with major histocompatibility complex antigens on thymic ECs in general, and on pale and intermediate subtypes in particular.

Animals↗
PubMed2005

Maturational stage-dependent thymocyte responses to TCR engagement.

Thymocyte positive and negative selection are dependent on avidity-driven TCR-mediated recognition events in the thymus. High-avidity recognition events result in negative selection, while low-avidity recognition events result in positive selection. However, it has not been established how thymocytes maturation stages affect their responses to TCR signals of different avidities. We gained insight into this question when we reduced thymocyte selection to an in vitro system, in which full maturation of developmentally synchronized immature double-positive thymocytes was induced on a cloned line of thymic epithelial cells. Our analysis of the kinetics of thymocyte development supports a multi-phasic model of thymic selection. In it, thymocyte maturation stages as well as interaction avidity control the outcome TCR stimulation. Positive selection is initiated during a primary recognition event that proceeds independently of the TCR avidity. During a secondary recognition event the final fate of thymocyte, full maturation versus negative selection, is determined by TCR avidity.

Animals↗
PubMed1990

In vivo and in vitro repertoire of CD3+CD4-CD8- thymocytes.

CD4-CD8- thymocytes contain a cell subset which expresses the complete CD3-TCR complex (alpha/beta or gamma/delta) of which the ontogeny and filiation are unknown. One of the questions is whether this population can be intrathymically selected, an obligatory step for the mature CD4+ and CD8+ cell differentiation pathway, or if the absence of CD4 an CD8 allows them to escape thymic selection. The repertoire of CD3+CD4-CD8- (CD3+ DN) thymocytes was analyzed in different strains of mice with different combinations of H-2 and Mls expression. The expression of V beta 8.1 in freshly isolated CD3+ DN cells is the highest in Mls-1b mice and the lowest in Mls-1a and F1 mice, suggesting that selection against this specificity can be achieved in vivo. By contrast, a low percentage of V beta 6+ cells is found in all the strains, with no correlation according to Mls expression. In vitro culture of DN thymocytes with IL-1 and IL-2 leads to the proliferation of CD3+ DN cells. In vitro culture amplifies the in vivo pattern of V beta 8.1 expression, while V beta 6+ cells only expand in DN cells of B6 and B10D2 Mls-1b mice with the same genetic background.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Interleukin-12 prevents severe acute graft-versus-host disease (GVHD) and GVHD-associated immune dysfunction in a fully major histocompatibility complex haplotype-mismatched murine bone marrow transplantation model.

BACKGROUND: We have recently reported that interleukin (IL)-12 prevents acute graft-versus-host disease (GVHD)-induced mortality in a full major histocompatibility complex- plus multiple minor antigen-mismatched A/J-->B10 bone marrow transplantation (BMT) model. Because most patients have access to a haploidentical, one haplotype-mismatched donor, we have now investigated the protective effect of IL-12 against GVHD and GVHD-associated immune dysfunction in a haploidentical CBD2F1 (H2kxd) --> B6D2F1 (H2bxd) strain combination. METHODS: GVHD was induced by injecting CBD2F1 marrow and spleen cells into lethally irradiated B6D2F1 mice. RESULTS: In untreated control mice, GVHD resulted in 87% mortality by day 8 after BMT, with no survivors beyond day 17. Treatment with a single injection of IL-12 on the day of BMT led to 87% long-term survival, with no significant weight loss, diarrhea or GVHD skin changes. The majority of T cells recovering in these mice showed the CD62L+, CD44low, CD45RBhigh naive phenotype. These T cells showed specific tolerance to both host and donor histocompatibility antigens, but normal anti-third party (H2s) alloresponses in vitro. B-cell proliferative responses to lipopolysaccharide were also normal in IL-12-protected mice. Moreover, normal negative selection of thymocytes bearing T cell receptors with Vbeta that recognize endogenous superantigens was observed among CD4+CD8- thymocytes, indicating a lack of GVHD-associated thymic selection abnormalities in IL-12-protected allogeneic BMT recipients. CONCLUSIONS: IL-12 provides permanent protection against an otherwise severe, rapidly lethal GVHD, with no clinical manifestations of chronic GVHD, immunosuppression or autoimmune features, in a full major histocompatibilty complex haplotype-mismatched murine BMT model.

Acute Disease↗
PubMed2001

Homogeneous epithelial gamma delta T cell repertoire of the skin is shaped through peripheral selection.

In contrast to the T cell receptor (TCR) diversity of major alpha beta T cells in lymphoid tissues, epithelial T cells of the murine skin, called dendritic epidermal T cells (DETC), express exclusively an invariant gamma delta TCR. Fetal thymic precursors of DETC immigrate to the skin before birth, and in adult mice T cells expressing the canonical gamma delta TCR identical to that of DETC are not found in other lymphoid or epithelial tissues. Here, we show that DETC precursors migrate to the gut as well as to the skin during fetal periods, but preferentially survive and expand in the skin after birth. We propose that similar to the thymic selection of the diverse alpha beta T cell repertoire, 'peripheral selection' of the homogeneous epithelial gamma delta T cell repertoire may be mediated by TCR signaling upon the recognition of the self-ligand, because the ligand for the DETC TCR was expressed only in the skin.

Animals↗
PubMed2002

Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection.

TCR signaling can result in cell fates ranging from activation to tolerance to apoptosis. Organization of molecules in an "immunological synapse" between mature T cells and APCs correlates with the strength of TCR signaling. To investigate synapse formation during thymic selection, we have established a reaggregate system in which molecular recruitment of GFP fusion proteins to thymocyte:stromal cell interfaces can be visualized in real time. We demonstrate that negative selection is associated with efficient conjugate formation and rapid recruitment of p56(lck) and CD3zeta to an immunological synapse. Interestingly, CD3zeta-GFP does not accumulate at the center of the synapse, as in mature T cells, but at the periphery across a wide range of ligand densities. This implicates differences in synapse geometry in initiation of alternate signals downstream of the TCR.

Animals↗
PubMed1997

A dominant-negative mutant of the Rab5 GTPase enhances T cell signaling by interfering with TCR down-modulation in transgenic mice.

TCR triggering results in the down-modulation of engaged receptors by endocytosis. As a result of this process, Ag-binding sites are depleted from the surface and signaling responses should be attenuated. To test the importance of TCR down-regulation on T cell signaling, we generated mice expressing a dominant-negative form of Rab5 (Rab5N133I) in T cells. Rab5, a monomeric GTPase of the Ras superfamily, has been implicated in the regulation of early steps in the endocytic pathway. In Rab5N133I mice, mature thymocytes developed, but the absolute number of CD4+CD8+ double positive thymocytes was reduced. Fluid phase endocytosis was severely impaired in the transgenic thymocytes. In peripheral T cells, the kinetics and rate of ligand-induced TCR down-modulation were delayed and reduced. These effects were correlated with enhanced early and late signaling responses. Analysis of thymocyte development in doubly transgenic mice for Rab5N133I and a lymphocytic choriomeningitis virus (LCMV) peptide-specific TCR demonstrated that TCR signaling was enhanced by dominant inhibition of Rab5 function, resulting in altered thymic selection. These findings suggest that TCR endocytosis is an important regulatory component of TCR signaling and that defects in this regulation can result in prolonged signaling and alter thymic development.

Animals↗
PubMed1997

Class I- and class II-reactive TCRs coexpressed on CD4+ T cells both trigger CD4/CD8-shared and CD4-unique functions.

CD4+ and CD8+ T cells emerge from thymic selection expressing a TCR restricted by MHC class II (TCRII) and MHC class I (TCRI), and upon Ag stimulation develop respectively into Th and CTL effector cells. The influence of thymic differentiation and antigenic stimulation on the determination of T cell functions was studied, with CD4+ T cells expressing a transgenic TCRI that reacts with the class I alloantigen H-2K(b) in a CD8-independent fashion. Such T cells additionally express a TCR, probably TCRII, in which the transgenic TCR beta-chain is associated with endogenously rearranged TCR alpha-chains. Upon in vitro stimulation with H-2K(b)-expressing cells, both CD8+ and CD4+ transgenic TCR+ T cells developed into CTL capable of killing Ag-expressing target cells through a perforin-dependent mechanism, and secreted IL-2 and IFN-gamma. Fas ligand-dependent killing could also be induced in both CD8+ and CD4+ in vitro stimulated T cells. The capacity to secrete IL-4 was restricted to the CD4+ T cells, however, suggesting that both CD8/CD4-shared and CD4-unique programs can be elicited by stimulation of CD4 T cells through a TCRI. Acquisition of CTL function was also induced upon class II alloantigen stimulation through the endogenously rearranged TCRII, which represents a polyclonal set of TCRs. IL-2, IFN-gamma, and after restimulation, IL-4, were also produced. Thus: 1) events associated with intrathymic selection influence the gene program activated in response to the same TCRI/APC interaction; and 2) CD4+ T cells expressing a TCRI and a TCRII can activate the same gene program after engagement of either one of these TCRs.

Animals↗