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PubMed1993

Selective thymocyte depletion in neonatal HIV-1 thymic infection.

OBJECTIVE: To determine the impact of HIV-1 infection on thymocyte development, and the role of thymic infection on the pathogenesis of neonatal HIV-1 infection. DESIGN AND METHODS: The consequences of thymic infection by HIV-1 were examined by comparative histologic and molecular analyses of an asymptomatic, HIV-1-seropositive 3-day-old subject, versus age- and treatment-matched controls. The presence of replicating virus was established by in situ hybridization with specific molecular probes to HIV-1. The distribution of thymocyte subsets was determined by quantitative flow cytometry following staining with antibodies to CD4 and CD8 cell surface proteins. RESULTS: The results show clear evidence of severe thymic involution, HIV-1 infection of thymocytes, and selective depletion of thymocyte subpopulations. The consequences of HIV-1 infection were a marked depletion of CD3+CD4+ CD8hi and CD3+CD4+CD8- cells. The phenotype of the residual thymic lymphoid population was predominantly that of immature CD3-CD4-CD8- double negative and CD3+CD4+CD8lo cells. CONCLUSION: Changes in the distribution of thymocyte subsets suggests a role for thymic involvement in the pathogenesis of HIV-1 infection in neonates.

CD3 Complex↗
PubMed1985

Selective lymphoid irradiation. V. Synergism with pretransplant thymectomy or thymic irradiation in cardiac transplantation in rats.

Selective lymphoid irradiation (SLI) using palladium-109-hematoporphyrin (Pd-H), given four days prior to transplantation, combined with two doses of antilymphocyte globulin (ALG) (10 mg, days -2 and -1), was evaluated as a method of induction of permanent heterotopic cardiac allograft survival in the highly histoincompatible rat strain combination of ACI (RT1(1))-to-Lewis (RT1a). Both Pd-H and ALG localize poorly in the thymus, so this study evaluated whether thymic irradiation (TI) or thymectomy (TX) of the adult recipient results in indefinite allograft survival. Immunosuppression with Pd-H or ALG alone gave a mean survival time (MST) of 6.7 +/- 0.6 days, but the combination of the two agents led to an MST of 17.6 +/- 3.4 days. When TI was combined with Pd-H and ALG, cardiac allograft survival was prolonged to 50.2 +/- 13.9 days, but TI alone showed an MST of 10.3 +/- 1.8 days. Permanent cardiac allograft survival (greater than 250 days) was achieved in all thymectomized recipients treated with the combination of Pd-H and a brief course of ALG. These animals also accepted second-set skin grafts and rejected third-party skin grafts following more than 150 days of ACI cardiac allograft survival. Thymic irradiation, although effective in acting synergistically with SLI and ALG, led to prolonged, but limited allograft survival, although thymectomy with SLI and ALG is synergistic in prolonging allograft survival permanently without chronic immunosuppression.

Animals↗
PubMed2005

Promiscuous thymic expression of an autoantigen gene does not result in negative selection of pathogenic T cells.

"Promiscuous" thymic expression of peripheral autoantigens can contribute to immunological tolerance in some cases. However, in this study we show that thymic mRNA expression alone cannot predict a contribution to thymic tolerance. Autoimmune gastritis is caused by CD4+ T cells directed to the alpha (H/Kalpha) and beta (H/Kbeta) subunits of the gastric membrane protein the H+/K+ ATPase. H/Kalpha mRNA is expressed in the thymus, but H/Kbeta expression is barely detectable. In this study, we demonstrate that thymic H/Kalpha in wild-type mice or mice that overexpressed H/Kalpha did not result in negative selection of pathogenic anti-H/Kalpha T cells. However, negative selection of anti-H/Kalpha T cells did occur if H/Kbeta was artificially overexpressed in the thymus. Given that H/Kalpha cannot be exported from the endoplasmic reticulum and is rapidly degraded in the absence of H/Kbeta, we conclude that H/Kalpha epitopes are unable to access MHC class II loading compartments in cells of the normal thymus. This work, taken together with our previous studies, highlights that thymic autoantigen expression does not necessarily result in the induction of tolerance.

Animals↗
PubMed1988

Thymic stroma-derived T cell growth factor: its role in the growth of immature thymocytes and T cell repertoire selection.

A newly established thymic stromal cell clone, MRL104.8a exhibited capacities to express Ia antigens and to support the growth of antigen-specific, interleukin-2 (IL-2)-dependent helper T cell (Th) clones without requirement of antigen and exogenous IL-2. Such growth was substituted by a factor produced into cultures by the MRL104.8a clone. This substance designated as thymic stroma-derived T cell growth factor (TSTGF) was demonstrated to be the protein that has an apparent molecular weight of about 25,000 and a pI of 6.0 and to be distinct from the previously described interleukins and cytokines. While the capacity of TSTGF to promote T cell proliferation was initially found by using various Th clones, further studies have demonstrated its capability of supporting the growth of immature (L3T4- Lyt-2-) thymocytes. TSTGF alone failed to function for the proliferation of double-negative thymocytes, whereas this novel growth factor was capable of inducing the proliferation of immature thymocytes by synergy with IL-1. Such growth promotion was further enhanced by the addition of IL-2 or IL-4 to cultures. The data were also presented that TSTGF could contribute to the clonal elimination in the thymus. The growth of a Th clone, 9-16, was supported on the TSTGF-producing and Ia-expressing MRL104.8a monolayer in the absence of the antigen against which this Th clone is directed. In contrast, the presence of the relevant antigen in the MRL104.8a culture elicited the lethal growth-inhibition of Th clone cells. Taken collectively, the results provide strong support for the proposition that TSTGF may play an essential role in the intrathymic T cell development in the context of T cell growth promotion and T cell repertoire selection.

Animals↗
PubMed1991

On the complexity of self.

Self peptides bound to self major histocompatibility complex (MHC) molecules have been implicated both in positive and in negative selection of T cells during intrathymic development. We report here that the novel MHC-restricted monoclonal antibody Y-Ae detects the MHC class II bound form of a major self peptide. Y-Ae binds approximately 12% of the relevant MHC class II molecules on self antigen presenting cells. The peptide detected by Y-Ae is one of several major peptides eluted from the MHC molecule. These data suggest that self peptides presented by self MHC class II molecules at densities sufficient to signal a CD4 T cell are of very limited complexity. Furthermore, as Y-Ae stains antigen presenting cells that mediate negative selection but not thymic cortical epithelial cells that drive positive selection, differential expression of self peptide:self MHC class II complexes may be a key feature of intrathymic selection.

Amino Acid Sequence↗
PubMed2001

A naturally processed mitochondrial self-peptide in complex with thymic MHC molecules functions as a selecting ligand for a viral-specific T cell receptor.

Peptide fragments of self-proteins bound to major histocompatibility complex molecules within the thymus are important for positively selecting T cell receptor (TCR)-bearing CD4(+)CD8(+) double positive (DP) thymocytes for further maturation. The relationship between naturally processed thymic self-peptides and TCR-specific cognate peptides is unknown. Here we employ HPLC purification of peptides released from H-2K(b) molecules of the C57BL/6 thymus in conjunction with mass spectrometry (MS) and functional profiling to identify a naturally processed K(b)-bound peptide positively selecting the N15 TCR specific for the vesicular stomatitis virus octapeptide (VSV8) bound to K(b). The selecting peptide was identified in 1 of 80 HPLC fractions and shown by tandem MS (MS/MS) sequencing to correspond to residues 68-75 of the MLRQ subunit of the widely expressed mitochondrial NADH ubiquinone oxidoreductase (NUbO(68-75)). Of note, the peptide differs at six of its eight residues from the cognate peptide VSV8 and functions as a weak agonist for mature CD8 single positive (SP) N15 T cells, with activity 10,000-fold less than VSV8. In N15 transgenic (tg) recombinase activating gene 2(-/)- transporter associated with antigen processing 1(-/)- fetal thymic organ culture, NUbO(68-75) induces phenotypic and functional differentiation of N15 TCR bearing CD8 SP thymocytes. Failure of NUbO(68-75) to support differentiation of a second K(b)-restricted TCR indicates that its inductive effects are not general.

Animals↗
PubMed2003

Efficient T cell repertoire selection in tetraparental chimeric mice independent of thymic epithelial MHC.

Nonthymic epithelial cells were compared with thymic epithelial cells for their role in T cell repertoire selection. Tetraparental aggregation chimeras were generated from T and B cell-deficient mice (H-2(d) SCID or H-2(b) Rag-/-) and thymus-deficient nude mice (H-2(b) or H-2(d)). These tetraparental mice showed primary protective CD8(+) T cell responses, after lymphocytic choriomeningitis virus infection, that were peptide-specifically restricted to either thymic or nonthymic epithelial MHC at comparable levels. These chimeras also mounted neutralizing IgG responses dependent on cognate CD4(+) T helper cell activity restricted to nonthymic epithelial MHC. Therefore, in contrast to earlier results with irradiation or thymus chimeras, these relatively undisturbed tetraparental mice reveal that the MHC of nonthymic epithelial cells efficiently selects a functional T cell repertoire.

Animals↗
PubMed1982

Homologies between cell interaction molecular controlled by major histocompatibility complex- and Igh-V-linked genes that T cells use for communication. Tandem "adaptive" differentiation of producer and acceptor cells.

We have asked the question: how do partner cells in immunoregulatory interactions between T cell subsets acquire the ability to recognize and react appropriately with one another? In particular, we have asked whether these communication events are completely determined by the cell's genetic constitution, or whether the recognition events can be learned during ontogeny. We have found that the T cells of parent into F1 chimeras and homozygous nude mice with F1 thymus grafts not only learn to react with genetically disparate acceptor cells, but that the receptors on the acceptor cells themselves learn to react with genetically disparate producer cells. This learning process can overcome both major histocompatibility complex- and immunoglobulin heavy chain variable region-linked restricted communication between T cell subsets. We interpret these findings to indicate that thymic elements can start a cascade of differential events. The thymic elements, whether endogenous or passively acquired, select from a pool of producer cells those that will react appropriately with the thymic selecting cells, and these cells become expanded. Then, the private markers (idiotype) on the expanded pool of producer cells act as selecting and expanding elements that choose from a pool of acceptor cells those that recognize the producer cells idiotype as self. This second differentiational event, although apparently thymus evidence that this type of acceptor cell differentiation could also take place during the course of an immune response.

Animals↗
PubMed2004

IL-12 inhibits thymic involution by enhancing IL-7- and IL-2-induced thymocyte proliferation.

IL-12 has been reported to affect thymic T cell selection, but the role of IL-12 in thymic involution has not been studied. We found that in vivo, IL-12b knockout (IL-12b(-/-)) mice exhibited accelerated thymic involution compared with wild-type (WT) B6 mice. This is characterized by an increase in thymocytes with the early development stage phenotype of CD25(-)CD44(+)CD4(-)CD8(-) in aged IL-12b(-/-) mice. Histologically, there were accelerated degeneration of thymic extracellular matrix and blood vessels, a significantly decreased thymic cortex/medulla ratio, and increased apoptotic cells in aged IL-12b(-/-) mice compared with WT mice. There was, however, no apparent defect in thymic structure and thymocyte development in young IL-12(-/-) mice. These results suggest the importance of IL-12 in maintaining thymic integrity and function during the aging process. Surprisingly, in WT B6 mice, there was no age-related decrease in the levels of IL-12 produced from thymic dendritic cells. Stimulation of thymocytes with IL-12 alone also did not enhance the thymocyte proliferative response in vitro. IL-12, however, provided a strong synergistic effect to augment the IL-7 or IL-2 induced thymocyte proliferative response, especially in aged WT and IL-12b(-/-) mice. Our data strongly support the role of IL-12 as an enhancement cytokine, which acts through its interactions with other cytokines to maintain thymic T cell function and development during aging.

Adjuvants, Immunologic↗
PubMed1998

Development of peptide-selected CD8 T cells in fetal thymic organ culture occurs via the conventional pathway.

Fetal thymic organ culture of TCR transgenic (Tg) tissue has been used to study issues of timing and specificity in T cell development. Because most TCR Tgs express a rearranged alphabeta TCR on the cell surface at an earlier stage in development than normal mice, there is a possibility that the conclusions of studies using TCR Tg cultures may not apply to normal development. In particular, in our studies of peptide-induced development of CD8 T cells, it is possible that the peptide acts on the immature double-negative cell, driving development of CD8 T cells without passing through a double-positive stage. This issue was examined by asking whether MHC class I restriction was required and by analyzing CD8beta levels and endogenous TCR alpha chain rearrangements. We found that if nonstimulatory peptides were used in fetal thymic organ culture, CD8 T cells developed via the conventional pathway, transiting through a double-positive stage. However, we could not rule out that cells selected in the presence of stimulatory peptides (agonists) did not develop directly from double-negative precursors.

Animals↗
PubMed1985

Induction of granulocytic hyperplasia, thymic atrophy, and hypercalcemia by a selected subpopulation of a murine mammary adenocarcinoma.

Three tumor cell subpopulation lines derived from a single, spontaneously occurring BALB/cfC3H mammary tumor were evaluated for their ability to cause a leukemoid effect in mice. One of the BALB/cfC3H tumor cell lines (410.4) produced leukocytosis with neutrophilia, hypercalcemia, and thymic atrophy. A second line (66) produced none of these effects. The third line (168) was intermediate in its ability to affect neutrophil counts and splenomegaly but did not produce thymic atrophy or hypercalcemia. These studies demonstrated that the hemopoietic effect of tumor cells derived from a single tumor was variable and that a tumor cell line which caused neutrophilia also induced hypercalcemia and thymic atrophy, the same association that was reported previously in the case of murine CE mammary carcinoma. These observations will be useful in the further investigation of pathophysiology of tumor-induced leukemoid reactions, hypercalcemia, and other paraneoplastic syndromes.

Adenocarcinoma↗
PubMed1999

A quantitative theory of affinity-driven T cell repertoire selection.

Binding of the T cell antigen receptor (TCR) to peptides presented on molecules encoded by major histocompatibility complex (MHC) genes is the key event driving T cell development and activation. Selection of the T cell repertoire in the thymus involves two steps. First, positive selection promotes the survival of cells binding thymic self-MHC-peptide complexes with sufficient affinity. The resulting repertoire is self-MHC restricted: it recognizes foreign peptides presented on self, but not foreign MHC. Second, negative selection deletes cells which may be potentially harmful because their receptors interact with self-MHC-peptide complexes with too high an affinity. The mature repertoire is also highly alloreactive: a large fraction of T cells respond to tissues harboring foreign MHC. We derive mathematical expressions giving the frequency of alloreactivity, the level of self-MHC restriction, and the fraction of the repertoire activated by a foreign peptide, as a function of the parameters driving the generation and selection of the repertoire: self-MHC and self-peptide diversity, the stringencies of positive and negative selection, and the number of peptide and MHC polymorphic residues that contribute to T cell receptor binding. Although the model is based on a simplified digit string representation of receptors, all the parameters but one relate directly to experimentally determined quantities. The only parameter without a biological counterpart has no effect on the model's behavior besides a trivial and easily preventable discretization effect. We further analyse the role of the MHC and peptide contribution to TCR binding, and find that their relative, rather than absolute value, is important in shaping the mature repertoire. This result makes it possible to adopt different physical interpretations for the digit string formalism. We also find that the alloreactivity level can be inferred directly from data on the stringency of selection, and that, in agreement with recent experiments, it is not affected by thymic selection.

HLA Antigens↗
PubMed2005

The Le Douarin phenomenon: a shift in the paradigm of developmental self-tolerance.

Ever since the foundations of Immunology, "self-tolerance" has remained a central issue in this field, pertaining to basic and clinical questions alike. Burnet and Medawar shared the Nobel Prize in 1960 for proposing that tolerance is induced by tissue antigens, if present during the development of the immune system during the embryonic/neonatal period. Very elegant experiments by Le Douarin and colleagues in the 1980's demonstrated that this is not the case; rather, the establishment of tolerance to peripheral tissues requires thymic epithelium which selects CD4 T lymphocytes mediating "dominant tolerance". The recent wealth of work on "regulatory T cells", as well as observations on the selective regulation of "tissue-specific" gene expression in thymic epithelial cells, confirm the critical relevance of those seminal findings in modern immunology.

Animals↗
PubMed1994

Thymic epithelial cell lines that mediate positive selection can also induce thymocyte clonal deletion.

Negative selection of potentially autoreactive thymocytes occurs mainly in the thymus and is thought to be induced primarily by interaction with bone marrow-derived cells. However, some studies have also reported a role for radioresistant thymic cells, which are probably epithelial in origin, in the deletion of thymocytes reacting to endogenous superantigens. We have previously demonstrated that thymic epithelial cell lines could induce thymocyte-positive selection in vivo. In this study, we assessed the potential of these cells to delete thymocytes reacting to the staphylococcal enterotoxin A or B superantigens in vitro. In the presence of staphylococcal enterotoxin A or B we found that all thymic epithelial cell lines used in this study were capable of activating T cell hybrids or deleting CD4+CD8+ thymocytes expressing an appropriate TCR. The extent of superantigen-mediated thymocyte deletion mediated by thymic epithelial cell lines was comparable to that mediated by a thymic macrophage cell line. Similar results were obtained with three phenotypically distinct thymic cell lines, suggesting that the ability to induce thymocyte deletion might be a general feature of various subsets of thymic epithelium. The observations provided in this study, combined with our previous demonstration that the same thymic epithelial cell lines can participate in positive selection, suggest that a given stromal cell population might be capable of taking part both in positive and negative selection of thymocytes.

Animals↗
PubMed1992

T-cell selection and T-cell receptor variable beta-chain usage in chronic hemodialysis patients.

Thymic and extrathymic selection processes are responsible for the shape of the T-cell repertoire. T-cell receptor (TCR) variable (V) chain usage, holding a place in tolerance, autoimmunity and response to external agents, was analyzed in 41 patients maintained on chronic hemodialysis treatment. Leukocyte (mean: 6444 +/- 2277 cells/microliters), lymphocyte (mean: 1457 +/- 707 cells/microliters) and T-cell (mean: 67 +/- 16%) counts were within expected limits, but hemodialysis patients showed an impressive increase of TCR V beta 6.7 positive peripheral blood lymphocytes (PBL) and a massive deletion of TCR V beta 8 positive PBL. V beta 6.7 positive PBL were detectable in all hemodialysis patients (n = 41, mean: 2.47 +/- 1.61% PBL) in contrast to a healthy population, where only 45% of subjects expressed V beta 6.7 on PBL (n = 9, mean: 3.50 +/- 1.83% PBL). Only 27% of our hemodialysis patients expressed V beta 8 on PBL (n = 11, mean: 1.00 +/- 1.94% PBL) in contrast to healthy subjects, who presented V beta 8 positive PBL (n = 20, mean: 2.89 +/- 1.23% PBL) in every case. Neither primary kidney disease, nor response to vaccination for hepatitis-B, nor dialyzer membranes used, were associated with these alterations of the TCR V beta-pool. It is likely, that the well-known impairment of the cytokine network in chronic renal failure, uremic toxins or response to infectious agents, may contribute to these different and possibly independent T-cell selection mechanisms in uremia.

Cell Separation↗
PubMed1994

Thymic CD45 tyrosine phosphatase regulates apoptosis and MHC-restricted negative selection.

The acquisition of immunologic self-tolerance is governed, in part, by selection mechanisms that occur during intrathymic T cell ontogeny. Although considerable data exist for the molecular basis of mature T cell signal transduction, the enzymes that participate in thymic TCR selection processes have remained unidentified. We report that augmented thymic expression of the CD45R0 protein tyrosine phosphatase increased the efficacy of TCR-mediated apoptosis and MHC-restricted negative selection of HY TCRs in vivo. Additionally, augmented CD45R0 expression resulted in the activation of endogenous p56lck tyrosine kinase in CD4+CD8+ thymocytes. These results identify a cellular enzyme, the CD45R0 protein tyrosine phosphatase, involved in the regulation of apoptosis and TCR selection mechanisms during CD4+CD8+ thymocyte differentiation.

Animals↗
PubMed1993

[Phenotypic analysis of immature T-lineage cells].

The characteristics of very immature T-lineage blasts including co-expression of myeloid properties and the distinctions between the phenotypes of pro-thymic (CD7+ CD5+ CD2+ CD3- CD4- CD8- or more immature) and thymic (CD3- CD4+ CD8+ or more mature) blasts are shown. The lineage-derivation of CD7+ CD5- CD2- and CD7+ CD5+ CD2- lymphoid blasts was investigated based on the gene expression of CD3 epsilon, CD3 delta and myeloperoxidase (MPO). The former group included 4 categories; undifferentiated blasts without commitment to myeloid or T-lineage, T-lineage blasts with mRNA of CD3 epsilon, T/myeloid blasts with mRNA of CD3 epsilon and MPO and blasts with mRNA of MPO. The latter included 2 categories; T-lineage blasts with CD3 epsilon and CD3 delta mRNA and T/myeloid blasts with CD3 epsilon, CD3 delta and MPO mRNA. Thus, CD3 epsilon was expressed at a more immature stage than CD3 delta. The blasts at the pro-thymic stage were different from those at the thymic stage in several respects. The T-cell receptor (TCR) beta-chain gene showed a germ-line configuration in most pro-thymic blasts. The CD13/CD33, CD11b and class II MHC antigens were expressed very frequently in the pro-thymic stage. The CD21 antigen was most selectively expressed at the thymic stage. Pro-thymic blasts were of RA type of CD45 antigen, while thymic blasts were of RO type. Recombination activation gene-1 (RAG-1) was only limitedly expressed at the pro-thymic stage, but was highly expressed at the thymic stage. These findings indicate that there are distinctive differences before and after the initiation of clonal selection which is unique and thymus-specific, and that the neoplastic cells represent each stage of T-lineage differentiation involving the unique thymic function.

Antigens, Surface↗