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J Sprent

Publications and source records attributed to J Sprent.

At least 109 records · Page 6Linked to original sources
PubMed1992

Growth of epithelial cells in the thymic medulla is under the control of mature T cells.

Epithelial cells in the thymic medulla are conspicuous in normal adult mice, but sparse in the early fetal thymus and the thymus of adult T cell-deficient SCID mice. To examine whether growth of medullary epithelial cells (MEC) depends upon local contact with mature T cells, we used the finding that the SCID thymus is unusually permeable to mature T cells entering from the bloodstream. When SCID mice received multiple injections of mature lymph node T cells from birth, the thymus accumulated large numbers of mature TCR+ T cells of resting phenotype, but contained virtually no immature (CD4+8+) cells. The injected T cells localized in the medullary region of the thymus and led to marked regeneration of MEC. These and other data suggest that the growth of MEC is under the control of mature T cells. Placing MEC under T cell control might be a device for regulating the size and integrity of the medulla, especially during the phase of rapid thymic growth. Maintaining the cellular components of the medulla in proper balance could be critical for ensuring efficient self tolerance induction.

Animals↗
PubMed1992

Thymus-grafted SCID mice show transient thymopoiesis and limited depletion of V beta 11+ T cells.

To seek direct evidence for the notion that stem cells in the thymus need to be constantly replenished from the bone marrow (BM), fetal (day 15) thymuses from normal BALB/c mice were grafted into T and B cell-deficient C.B-17 SCID mice (both H-2d, I-E+). The thymus grafts in these mice showed normal thymopoiesis for the first 3 wk postgrafting but then developed sudden atrophy with near complete loss of CD4+8+ cells by 4-5 wk. Such atrophy was not seen when the thymus-grafted mice were cotransplanted with normal BM cells. The lymph nodes of SCID mice receiving thymus grafts alone contained mature T cells but virtually no B cells. This lack of B cells was associated with aberrant I-E-restricted V beta deletion: the depletion of V beta 3+ and V beta 5+ T cells was near complete, whereas V beta 11+ cells showed only marginal depletion.

Animals↗
PubMed1992

Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an experimentally induced demyelinating disease mediated by CD4+ T cells specific for various myelin proteins including myelin basic protein (MBP) and myelin proteolipid protein (PLP). Although myelin- and other CNS-specific antibodies are produced in EAE, B cells and antibodies are thought by most not to play a decisive role in the induction of EAE. In this report we show that B cells serve as the major antigen-presenting cells (APC) during the T cell activation stage in lymph nodes, and that MBP-specific antibodies can greatly enhance the induction of EAE. The role of B cells as APC is demonstrated in B cell-depleted mice. EAE cannot be induced by antigen/complete Freund's adjuvant immunization unless these mice are locally reconstituted with B cells prior to immunization. The enhancing effect of antibodies is demonstrated in experiments in which EAE is induced by the adoptive transfer of encephalitogenic T cells. The adoptive transfer of large numbers of encephalitogenic T cells induces EAE in 90% of normal recipient mice, but only 33% of B cell-depleted mice get EAE at the same cell dose. The efficiency of EAE induction in B cell-depleted mice can be enhanced if MBP-specific antibodies are simultaneously administered. A similar enhancement is also seen in normal mice when the number of adoptively transferred T cells is limiting. We propose that MBP-specific antibodies enhance the presentation of myelin-derived antigens by APC in the CNS to the adoptively transferred encephalitogenic T cells.

Animals↗
PubMed1992

An unusual class II molecule.

H-2O is a recently described non-polymorphic mouse MHC class II molecule. Here, Lars Karlsson and colleagues describe the discovery of the H-2Ob and H-2Oa loci and the pattern of expression of H-2O, and speculate on the possible function of this unusual molecule.

Animals↗
PubMed1992

Factors influencing the fate of T cells responding to Mls antigens.

Although T cell tolerance to self antigens is primarily a reflection of clonal deletion in the thymus, recent evidence suggests that mature T cells are subject to negative regulation in the post-thymic environment: Extrathymic tolerance is the result of clonal anergy in some studies and T cell deletion in others. The factors controlling the induction of anergy versus deletion of mature T cells are still poorly understood. This article summarizes evidence that exposure of T cells to Mls superantigens in vivo leads to a sequence of T cell proliferation, anergy and deletion; anergy appears to reflect persistence of antigen. The biochemical consequences of exposing T cells to superantigens in vitro are discussed.

Animals↗
PubMed1992

T cell tolerance after bone marrow transplantation in mice.

This article provides a brief overview of T cell tolerance induction in the thymus, using parent----F1 bone marrow (BM) chimeras as a model. Although intrathymic tolerance is controlled largely by BM-derived cells, experiments with BM chimeras suggest that thymic epithelial cells can make a major contribution to tolerance induction, especially for high-affinity T cells. Whether extrathymic mechanisms contribute to tolerance induction remains controversial: evidence against this possibility is provided by the finding that transferring normal parental strain T cells to parent----F1 chimeras leads to immunogenicity rather than tolerogenicity. Breakdown of self tolerance is discussed in terms of the phenomenon of "auto-GVHD".

Animals↗
PubMed1991

Long-term xenogeneic chimeras. Full differentiation of rat T and B cells in SCID mice.

To test whether T and B cell differentiation can proceed across species barriers, rat fetal liver (FL) cells were used to reconstitute SCID mice. Provided that the hosts were conditioned with light irradiation, i.v. injection of FL cells caused near-complete repopulation with rat-derived lymphohematopoietic cells, including myeloid and erythroid cells, Ia+ cells of the macrophage/dendritic cell lineages, and mature T and B cells. In keeping with the known hypersensitivity of SCID cells to irradiation, host hematopoietic cells in the chimeras were almost undetectable, even with hosts exposed to as low as 250 rad. In the case of T cells, the distribution of immature and mature cells in the thymus of rat FL----SCID chimeras closely resembled the normal rat thymus in terms of architecture and expression of CD4, CD8, and alpha beta-TCR molecules. Thymopoiesis was followed by the appearance of large numbers of typical rat CD4+ and CD8+ cells in spleen and lymph nodes. These organs also contained substantial numbers of rat B (mu+) cells. The data thus indicate that the xenogeneic environment of SCID mice is fully capable of sustained de novo differentiation of rat T and B cells.

Animals↗
PubMed1991

Mature murine B and T cells transferred to SCID mice can survive indefinitely and many maintain a virgin phenotype.

To seek information on the potential lifespan of normal B and T lymphocytes, lymph node (LN) cells from unprimed mice were transferred to H-2-identical severe combined immunodeficiency (SCID) hosts. At a population level, the donor B and T cells survived for at least 10 mo post-transfer with no reduction in their numbers. In terms of antibody production, LN-injected SCID mice remained responsive to several different antigens and contained unprimed precursors of memory cells for greater than or equal to 6 mo post-transfer. Most of the B and T cells recovered from LN-injected SCID mice expressed the typical virgin phenotype of mature lymphocytes from young mice. These findings suggest that many of the transferred lymphocytes might have remained in interphase as virgin cells from the time of injection. This did not apply to all of the transferred cells, however, because 20-40% of CD4+ cells from long-term SCID hosts displayed a memory phenotype, 7% incorporated 2-bromodeoxyuridine over 5 d, and total numbers of B and T cells increased gradually (twofold) over a 10-mo period. Collectively, the data favor the view that the pool of mature B and T cells in adult mice is largely self sufficient: some of the cells proliferate, presumably in response to environmental antigens, but many mature cells can remain quiescent for prolonged periods. Input of new cells from the primary lymphoid organs continues, but at a much reduced rate relative to young life.

Animals↗
PubMed1991

T cell contact with Ia antigens on nonhemopoietic cells in vivo can lead to immunity rather than tolerance.

Long-term H-2-heterozygous a----(a x b)F1 bone marrow (BM) chimeras prepared with supralethal irradiation (1,300 rad) are devoid of Ia+ host BM-derived antigen-presenting cells (APC), but show quite strong host Ia expression in germinal centers, probably on follicular dendritic cells (a class of nonhemopoietic stromal cells). To examine whether Ia expression on these non-BM-derived cells is capable of inducing post-thymic tolerance of T cells, thymectomized irradiated (a x b)F1 mice were reconstituted with parent alpha stem cells and then, 6 mo later, given parent alpha thymus grafts. As measured by primary mixed lymphocyte reactions and V beta expression, the CD4+ cells differentiating in the thymus-grafted mice showed no detectable tolerance to the H-2 (Ia) antigens of the host. To examine whether the thymus-grafted mice contained immunologically significant quantities of host Ia antigens, long-term alpha----(alpha x b)F1 chimeras were injected with normal strain alpha CD4+ cells; the donor cells were recovered from thoracic duct lymph of the chimeras and tested for host reactivity in vitro. The results showed that Ia expression in the chimeras was sufficient to cause selective trapping of a substantial proportion of host-Ia-reactive CD4+ cells soon after transfer and, at later stages, to induce strong priming. Tolerance was not seen. The data place constraints on the view that T cell recognition of antigen expressed on cells other than typical BM-derived APC leads to tolerance induction.

Animals↗
PubMed1991

A novel class II MHC molecule with unusual tissue distribution.

The repertoire of mature class II-restricted T cells is generated through a complex process of selection whereby early T cells confront class II molecules in the thymus, especially on epithelial cells. Expression of class II molecules on such cells is prominent both in the cortex and in the medulla. We have identified a novel class II molecule, H-20, which is expressed only in epithelial cells of the thymic medulla and in B cells. The unusual tissue distribution and the nonpolymorphic nature of H-20 suggest that its function is different from that of classical class II molecules.

Amino Acid Sequence↗
PubMed1991

Reentry of T cells to the adult thymus is restricted to activated T cells.

To seek information on the capacity of mature T cells to migrate to the thymus, mice were injected with Thy-1-marked populations enriched for resting T cells or T blast cells; localization of the donor cells in the host thymus was assessed by staining cryostat sections of thymus and by FACS analysis of cell suspensions. With injection of purified resting T cells, thymic homing was extremely limited, even with injection of large doses of cells. By contrast, in vivo generated T blast cells migrated to the thymus in substantial numbers. Thymic homing by T blasts was greater than 50-fold more efficient than with resting T cells. Blast cells localized largely in the medulla and remained in the thymus for at least 1 mo post-transfer. Interestingly, localization of T blasts in the thymus was 10-fold higher in irradiated hosts than normal hosts. Thymic homing was especially prominent in mice injected with T blasts incubated in vitro with the DNA precursor, 125I-5-iodo-2'deoxyuridine (125IDUR); with transfer of 125IDUR-labeled blasts to irradiated hosts, up to 5% of the injected counts localized in the host thymus. These data suggest that thymic homing by T blasts might be largely restricted to cells in S phase. The physiological significance of blast cell entry to the thymus is unclear. The possibility that these cells participate in intrathymic tolerance induction is discussed.

Animals↗
PubMed1991

Graft-versus-host disease in experimental allogeneic bone marrow transplantation.

Considerable progress has been made in defining the relative contributions of CD4+ and CD8+ cells to GVHD. Studies in mice have shown that, in isolation, each T cell subset is able to induce lethal GVHD in irradiated hosts. For hosts differing at the MHC (H-2), CD4+ cells cause GVHD directed to H-2 class II antigens whereas CD8+ cells produce GVHD to H-2 class I antigens. With H-2-matched hosts expressing multiple minor H antigens, induction of lethal GVHD is largely under the control of CD8+ cells. Which particular minor H antigens provide the targets for GVHD in mice is still unclear. Clarifying this question is complicated by the finding that the target antigens for GVHD do not necessarily correlate with the targets for cytotoxicity measured in vitro; moreover, immunodominance occurs when T cells are exposed to multiple minor H antigens in vivo. In terms of clinical application, there is a need to devise animal models for improving the success of HLA-matched bone marrow transplantation. Selectively depleting the marrow inoculum of CD8+ cells and preimmunizing the donor against viral pathogens are two procedures which are currently under study.

Animals↗
PubMed1991

Characterization of target injury of murine acute graft-versus-host disease directed to multiple minor histocompatibility antigens elicited by either CD4+ or CD8+ effector cells.

The precise identity of effector mononuclear cells capable of eliciting acute graft-versus-host disease (AGVHD) is controversial. In this study, highly purified subsets of donor T cells were used to produce AGVHD to multiple minor histocompatibility (H) antigens in two strain combinations of mice matched for the major histocompatibility complex (MHC). In the C3H.SW- greater than B6 strain combination, only CD8+ effector cells produced histologic evidence of AGVHD in skin and liver, which peaked 3 weeks after transplant. In the B10.D2- greater than DBA/2 strain combination, CD4+ effector cells, and to a lesser extent, CD8+ cells, mediated disease in skin, liver, and intestine, which peaked during the fourth week after transplant. Analysis of skin and liver from both combinations showed target cell injury that was phenotypically similar and resembled that previously described in human disease in other studies. In addition, prominent epithelial injury also was detected in oropharyngeal mucosa, esophagus, hepatobiliary ducts, and seminal vesicle in both transplant settings. These findings indicate that functionally different subsets of donor T cells may be capable of initiating common pathways of cellular injury in selected target sites in AGVHD, and have potential implications for strategies that seek to ablate disease development by manipulation of donor marrow before transplantation.

Acute Disease↗
PubMed1990

Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity.

The mechanism by which T lymphocytes are tolerized to self or foreign antigens is still controversial. Clonal deletion is the major mechanism of tolerance for immature thymocytes; for mature T cells, tolerance is considered to reflect anergy rather than deletion, and to be a consequence of defective presentation of antigen. This paper documents a novel form of tolerance resulting when mature T cells encounter antigen in immunogenic form. Evidence is presented that exposure of mature T cells to Mlsa antigens in vivo leads to specific tolerance and disappearance of Mlsa-reactive V beta 6+ T cells. Surprisingly, the clonal elimination of V beta 6+ cells is preceded by marked expansion of these cells. Thus, tolerance induction can be the end result of a powerful immune response. These data raise important questions concerning the relationship of tolerance and memory.

Animals↗
PubMed1990

Induction of neonatal tolerance to Mlsa antigens by CD8+ T cells.

Antigen-specific tolerance of T cells to minor lymphocyte stimulatory (Mls) antigens can be induced in mice by neonatal injection of foreign lymphohematopoietic cells. Although immune responses to Mlsa antigens are controlled by B cells, CD8+ T cells were the most effective cell type for induction of Mlsa tolerance. Tolerance was evident in both thymus and lymph nodes and could be induced by as few as 2 x 10(4) CD8+ T cells; these cells were 50 to 100 times as potent as CD4+ cells or B cells in causing functional tolerance and deletion of V beta 6+ T cells. Thus, intrathymic contact with antigens expressed on CD8+ T cells may play an important role in controlling the normal development of tolerance.

Animals↗
PubMed1990

T cell reactivity to MHC molecules: immunity versus tolerance.

The specificity of mature CD8+ and CD4+ T lymphocytes is controlled by major histocompatibility complex (MHC) class I and class II molecules, respectively. The MHC class specificity of T cells is stringent in many assays, but is less evident when cells are supplemented with exogenous lymphokines. The repertoire of T cells is shaped through contact with MHC molecules in the thymus and involves a complex process of positive selection and negative selection (tolerance). Tolerance of immature T cells to MHC molecules can reflect either clonal deletion or anergy and results from intrathymic contact with several cell types, including epithelial cells and cells with antigen-presenting function. Unlike immature T cells, mature T cells are relatively resistant to tolerance induction. In certain situations partial unresponsiveness of mature T cells can be achieved by exposing T cells to foreign MHC molecules expressed on atypical antigen-presenting cells. Tolerance is rarely complete, however, and the precise requirements for tolerizing mature T cells are still unclear.

Animals↗