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J Sprent

Publications and source records attributed to J Sprent.

At least 91 records · Page 5Linked to original sources
PubMed1994

Turnover of naive- and memory-phenotype T cells.

On the basis of their surface markers, T lymphocytes are divided into subsets of "naive" and "memory cells". We have defined the interrelationship and relative life spans of naive and memory T cells by examining the surface markers on murine T cells incorporating bromodeoxyuridine, a DNA precursor, given in the drinking water. Three findings are reported. First, using a new method we show that the release of newly formed naive T cells from the unmanipulated thymus is very low (confirming the findings of others with surgical approaches). Second, in thymectomized mice, T cells with a naive phenotype remain in interphase for prolonged periods; however, some of these cells divide and retain (or regain) their "naive" markers. Third, most T cells with a memory phenotype divide rapidly, but others remain in interphase for many weeks. Collectively, the data indicate that long-lived T cells have multiple phenotypes and contain a mixture of memory cells, naive (virgin) cells, and memory cells masquerading as naive cells.

Administration, Oral↗
PubMed1994

B7 expression on thymic medullary epithelium correlates with epithelium-mediated deletion of V beta 5+ thymocytes.

Recent evidence suggests that I-E+ thymic epithelium, especially medullary epithelium, can induce partial deletion of superantigen-reactive T cells expressing TcR V beta 5, V beta 11, and V beta 17. To seek further information on this issue, we constructed bone marrow chimeras in which MHC class II I-E is expressed on thymic epithelial cells at various levels and locations; the chimeras were reconstituted with stem cells from TcR V beta 5 transgenic mice. Intrathymic deletion of V beta 5 T cells was restricted to relatively mature T cells (expressing high TcR levels), and the degree of deletion correlated with the density of I-E expression in the thymic medulla rather than in the thymic cortex; selective I-E expression in medullary epithelium caused prominent deletion. Interestingly, immunostaining of normal and chimeric mice revealed that expression of B7 (the ligand for CD28) is largely restricted to a subset of medullary epithelial cells; these cells are I-E+ and co-express a specific carbohydrate bound by the lectin UEA-1. B7 expression was lower in thymuses of class II-deficient mice (A beta b-/-) and T-cell-deficient mice (SCID), suggesting that B7 expression is up-regulated during CD4+ thymocyte selection. In support of this idea, B7 expression in the thymus was restored to a normal level in bone marrow reconstituted SCID mice. Because B7 expression correlates with a costimulatory signal for T cells, selective expression of B7 and related antigens on I-E+ medullary epithelium may explain why these cells play a more prominent role in V beta deletion than cortical epithelium.

Animals↗
PubMed1994

Expansion/deletion of mature T cells exposed to endogenous superantigens in vivo.

Previous studies have shown that in thymectomized hosts exposure of mature T cells to Mlsa (mtv-7) Ag in vivo leads to specific tolerance and the disappearance of Mlsa-reactive V beta 6+ T cells after an initial phase of T cell expansion. To investigate the factors controlling postthymic elimination of mature T cells, we examined T cell responses to Mlsa and other endogenous superantigens in a number of different strain combinations. The results show that the extent of T cell expansion/deletion is influenced by various factors, including the H-2 haplotype of the host and the particular V beta studied. Collectively, the results suggest that the extent of elimination of mature T cells is variable and may be a function of high avidity interactions with APC.

Animals↗
PubMed1994

Rat T cell response to superantigens. I. V beta-restricted clonal deletion of rat T cells differentiating in rat-->mouse chimeras.

T cells of mice display V beta-specific reactivity for a spectrum of mouse mammary tumor virus (Mtv) antigens; confrontation with these antigens during ontogeny causes substantial "holes" in the T cell repertoire. Since endogenous Mtv antigens are rare in other species, the question arises whether V beta-specific recognition of Mtv antigens is unique to mice. To examine this question, rat T cells were allowed to differentiate from stem cells in severe combined immunodeficiency (SCID) mice. These rat-->mouse xenochimeras were prepared under a variety of conditions. The results show that rat T cells are strongly reactive to mouse Mtv antigens, both in terms of tolerogenicity and immunogenicity. In fact, the V beta specificity of rat and mouse T cells for Mtv antigens is almost indistinguishable.

Animals↗
PubMed1994

Rat T cell responses to superantigens. II. Allelic differences in V beta 8.2 and V beta 8.5 beta chains determine responsiveness to staphylococcal enterotoxin B and mouse mammary tumor virus-encoded products.

The previous paper in this series demonstrates that rat T cells developing de novo in the presence of mouse mammary tumor virus (Mtv) antigens in rat-->severe combined immunodeficiency (SCID) mouse xenochimeras display a distinct pattern of V beta-restricted deletion; this deletion pattern is remarkably similar to that occurring during thymic development of mouse T cells in Mtv+ strains. In addition, T cells developing in the absence of Mtv antigens in these rat-->mouse xenochimeras are tolerant of host antigens, but show strong primary proliferative responses in cultures stimulated with Mtv-7+ (Mlsa) mouse cells; like the mouse, these rat T cell responses are dominated by V beta 6 and V beta 8 T cells. Here, we continue analysis of rat T cell responses to superantigens; we show that T cells from Lewis and Fischer 344 rats expressing V beta 8.2 display an important all-or-nothing difference in their responses to Mtv-7 superantigens. This all-or-none strain difference in the response to Mtv-7 applies also to the response by V beta 8.2 and V beta 8.5 T cells to the soluble superantigen staphylococcal enterotoxin B. Because these two rat strains express different alleles of these two V beta 8 family members, this finding identifies additional, hitherto unreported residues of the T cell receptor beta chain important in T cell responses to superantigens.

Alleles↗
PubMed1994

The role of host T cell subsets in bone marrow rejection directed to isolated major histocompatibility complex class I versus class II differences of bm1 and bm12 mutant mice.

An expanded pool of unrelated donors (URD) is now being utilized for clinical allogeneic bone marrow transplantation. Because URD transplants can involve a mismatch at least at one genotypic MHC locus, we developed a C57BL/6 congenic mouse model to better understand graft rejection based exclusively on MHC class I or class II disparities. T cell-depleted (TCD) BM from class II-disparate mutant bm12 mice was transplanted into irradiated C57BL/6-Ly5.2 congenic hosts. These mice express a different allelic form of the Ly5 (CD45) marker than bm12 and thus permit definitive typing of reconstituted mice by flow cytometry. Peripheral blood typing indicated that host-mediated graft rejection was restricted to class II-reactive CD4+ cells since an anti-CD4 monoclonal antibody significantly inhibited rejection by enhancing the level of mean donor cell engraftment from 13% to 53%. The administration of anti-CD8 had no inhibitory effect on the ability of the recipient to reject the donor graft. Hematologic reconstitution studies revealed that there was a direct relationship between the level of donor cell engraftment and the extent of lymphoid, myeloid, and erythroid recovery. Mice that did not engraft had sustained reductions in in hematologic recovery. In other studies, TCD BM from bm1 mice mutated only in the MHC class I region was rejected by C57BL/6-Ly5.2 recipients. Anti-CD8 mAb infusion prevented the class I response resulting in an increase in the level of mean donor cell engraftment from 1% to 78%. Anti-CD4 alone had no effect. A CD4/CD8 T cell interaction could be important since the combination of anti-CD4 and anti-CD8 mAb resulted in significantly better donor engraftment than with the individual antibodies. Since the role of NK cells in these models has not been previously established and there is a reported association between NK cells and the rejection of BM cells that lack the expression of self-MHC antigens, we tested the role of NK cells. The elimination of NK cells using anti-NK mAb had no effect on graft rejection in either the bm1 or bm12 model. In addition to their value in exploring mechanisms of graft rejection, these models may prove useful for evaluating the efficacy of anti-BM rejection agents exclusively against class I- or class II-restricted disparities.

Alleles↗
PubMed1993

Tolerance of CD8+ T cells developing in parent-->F1 chimeras prepared with supralethal irradiation: step-wise induction of tolerance in the intrathymic and extrathymic environments.

Tolerance of CD8+ cells was examined in parent-->F1 bone marrow chimeras (BMC) prepared with supralethal irradiation; host class I expression in the chimeras was limited to non-BM-derived cells. In terms of helper-independent proliferative responses in vitro and induction of graft-vs.-host disease on adoptive transfer, CD8+ cells from long-term chimeras showed profound tolerance to host antigens irrespective of whether the cells were prepared from the thymus or from spleen or lymph nodes. By limiting dilution analysis, cytotoxic T lymphocyte (CTL) precursors specific for host antigens were rare in the extrathymic lymphoid tissues. In the thymus, by contrast, host-specific CTL precursors were only slightly less frequent than in normal parental strain mice. These host-specific CD8+ cells survived when BMC thymocytes were transferred intravenously to a neutral environment, i.e., to donor strain mice. When transferred to further BMC hosts, however, most of the host-reactive cells disappeared. Collectively, the data suggest that tolerance of CD8+ cells in BMC hosts occurs in both the intrathymic and extrathymic environments. In the thymus, contact with host antigens on thymic epithelial cells deletes CD8+ cells controlling helper-independent proliferative responses and in vivo effector functions but spares typical helper-dependent CTL precursors. After export from the thymus, most of the CTL precursors are eliminated after contacting host antigens on stromal cells in the extrathymic environment.

Animals↗
PubMed1993

Exclusion of circulating T cells from the thymus does not apply in the neonatal period.

Although T cells arise in the thymus, migration of mature postthymic T cells back to the thymus is very limited in adult mice and is restricted to activated cells. In neonates, by contrast, we present evidence that circulating CD4+ and CD8+ T cells with a naive/resting phenotype readily enter the thymus after intravenous injection and remain there for prolonged periods. The migration of resting T cells to the neonatal thymus is largely limited to an unusual subset of cells which lacks expression of the lymph node homing receptor, leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) (MEL-14). Migration of mature T cells to the thymus in neonates may be important for self-tolerance induction.

Age Factors↗
PubMed1993

Lifespans of naive, memory and effector lymphocytes.

Typical T and B lymphocytes in the secondary lymphoid organs are long-lived cells that are selected from a large pool of short-lived precursor cells in the primary lymphoid organs. The bulk of mature T and B cells are immunologically naive and remain in interphase for prolonged periods. Contact with specific antigen causes these naive cells to proliferate rapidly and differentiate into a mixture of short-lived effector cells and long-lived memory cells. Memory cells have a rapid turnover, and the survival of these cells appears to require persistent contact with antigen.

Animals↗
PubMed1993

Intrathymic and extrathymic tolerance in bone marrow chimeras.

Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

T cell tolerance and self/nonself discrimination.

T cell tolerance to self antigens is at least partly a reflection of clonal deletion of immature T cells in the thymus. Although it is well accepted that intrathymic tolerance is primarily a reflection of T cell contact with bone-marrow (BM)-derived antigen-presented cells (APC), evidence is presented that thymic epithelial cells (TEC) can contribute to tolerance induction. Studies with thymocytes from BM chimeras suggest that selective contact with antigen on TEC induces clonal deletion of a subset of high-affinity T cells; these cells are primarily responsible for in vivo effector functions such as allograft rejection and induction of lethal graft-versus-host disease. Intrathymic contact with TEC fails to delete the typical low-affinity T cells which mediate cytotoxic responses in vitro when cultured with lymphokines. Deletion of these low-affinity T cells appears to require contact with BM-derived APC. Despite the evidence that self tolerance involves clonal deletion in the thymus, it is often stated that backup mechanisms for tolerance induction must exist in the post-thymic environment, but this has yet to be proved. The competing argument is that normal self/nonself discrimination is solely a reflection of intrathymic tolerance: the failure of T cells to react against tissue-specific antigens is not a reflection of post-thymic tolerance but simply that T cells and tissue-specific antigens are kept segregated.

Animals↗
PubMed1992

Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo.

To test whether unprimed CD8+ cells can recognize class I alloantigens presented selectively on non-bone marrow (BM)-derived cells, unprimed parental strain CD8+ cells were transferred to long-term parent-->F1 BM chimeras prepared with supralethal irradiation. Host class I expression in the chimeras was undetectable on BM-derived cells and, in spleen, was limited to low-level staining of vascular endothelium and moderate staining of follicular dendritic cells (a population of nonhemopoietic cells in germinal centers). Despite this restricted expression of antigen, acute blood-to-lymph recirculation of parental strain T cells through the chimeras led to selective trapping of 95% of CD8+ cells reactive to normal F1 spleen antigen presenting cells (APC) in vitro. Subsequently, a small proportion of the trapped cells entered cell division and gave rise to effector cells expressing strong host-specific CTL activity. The activation of host-specific CD8+ cells was also prominent in double-irradiated chimeras, and cell separation studies showed that the effector cells were generated from resting precursor cells rather than from memory-phenotype cells. It is suggested that the non-BM-derived cells in the chimeras acted as semiprofessional APC. These cells were nonimmunogenic for most host-reactive CD8+ cells but were capable of stimulating a small subset of high-affinity T cells. The possible relevance of the data to the prolonged immunogenicity of vascularized allografts in humans is discussed.

Animals↗
PubMed1992

Two subsets of epithelial cells in the thymic medulla.

Information was sought on the features of epithelial cells in the murine thymic medulla. The expression of major histocompatibility complex (MHC) molecules on medullary epithelium was defined by light microscopy with the aid of bone marrow chimeras and MHC-transgenic mice. A proportion of medullary epithelial cells was found to show conspicuously high expression of conventional MHC (H-2) class I (K, D, L) and class II (I-A, I-E) molecules. These cells express a high density of the Y-Ae epitope, a complex of an E alpha peptide and I-Ab molecules found on typical bone marrow-derived cells. MHC+ medullary epithelial cells show limited expression of I-O molecules, a class of atypical nonpolymorphic MHC-encoded class II molecules present on B cells. Other medullary epithelial cells express a high density of I-O molecules but show little or no expression of typical MHC class I or II molecules. MHC and I-O expression thus appear to subdivide medullary epithelial cells into two phenotypically distinct subsets. This applies in adults. In the embryonic thymus most medullary epithelial cells express both types of molecules.

Animals↗