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J Sprent

Publications and source records attributed to J Sprent.

At least 145 records · Page 8Linked to original sources
PubMed1988

Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. I. L3T4+ cells can either augment or retard GVHD elicited by Lyt-2+ cells in class I different hosts.

Detailed information was sought on the capacity of purified Lyt-2+ cells to mediate lethal graft-versus-host disease (GVHD) directed to class I H-2 differences. When B6 Lyt-2+ cells were transferred to irradiated class I-different (B6 x bm 1)F1 mice, three different patterns of lethal GVHD were observed. First, rapid death from hematopoietic failure occurred when Lyt-2+ cells were transferred together with host-type marrow cells; this form of GVHD probably reflected direct destruction of stem cells by Lyt-2+ cytotoxic cells. Second, a pattern of late-onset, chronic GVHD resulting in death only after 4-6 wk occurred when Lyt-2+ cells were supplemented with donor marrow. This syndrome developed in the apparent absence of L3T4+ cells and was observed with either high or low doses of Lyt-2+ cells and with either light or heavy irradiation of the host. Third, an acute form of GVHD resulted when Lyt-2+ cells plus donor marrow cells were supplemented with exogenous help, i.e., by adding small doses of donor L3T4+ cells or injecting the hosts with rIL-2. Although L3T4+ cells potentiated GVHD when injected in small doses, supplementing Lyt-2+ cells with large doses of L3T4+ cells paradoxically led to marked protection; symptoms of GVHD were mild and no deaths occurred.

Animals↗
PubMed1988

T-cell selection in the thymus.

Differentiation of early thymocytes into mature T cells depends upon intrathymic T cell contact with major histocompatibility complex (MHC) molecules, i.e., H-2 molecules in mice. T cell recognition of H-2 molecules in the thymus has two consequences. First, some T cells undergo a process of positive selection which leads specifically-reactive immature thymocytes to survive and differentiate into mature functional T cells. Second, T cells with high affinity for H-2 molecules undergo negative selection (tolerance). We and others have argued that positive selection is controlled by thymic epithelial cells, especially cortical epithelium, whereas negative selection reflects contact with bone-marrow (BM) derived cells. This scheme appears to be an oversimplication because we have recently found evidence that a non-BM-derived component of the thymus, presumably epithelial cells, is highly tolerogenic for CD4+ cells. Whether tolerance of CD4+ cells is controlled by cortical epithelium or medullary epithelium is unclear. In this respect it is of interest that chronic injection of mice with cyclosporine A results in selective destruction of medullary epithelial cells and impaired induction of self tolerance.

Animals↗
PubMed1987

Unresponsiveness of MRL/MP-lpr/lpr mice to antigen given subcutaneously in adjuvant: partial restoration of response after local injection of B cells.

MRL/lpr mice were used as a model for seeking information on the role of B cells as antigen-presenting cells in vivo. In confirmation of the finding of other workers, MRL/lpr mice with pronounced lymphadenopathy failed to undergo T cell priming in lymph nodes (LN) after s.c. injection of keyhole limpet hemocyanin (KLH) in complete Freund's adjuvant (CFA): thus, in contrast to normal mice or young MRL/lpr mice, the LN cells from older MRL/lpr mice failed to give secondary T proliferative responses to the injected antigen in vitro. Because previous work from this laboratory has shown that B cells play a major role in priming T cells in LN of normal mice, we tested the possibility that the lack of T cell priming to KLH seen in older MRL/lpr LN reflected the relative paucity of B cells. To test this idea, MRL/LPR mice were injected s.c. with B cells taken from normal or young MRL/lpr mice 1 day before priming with KLH/CFA. In the case of old (20 to 24 wk) MRL/lpr mice with massive lymphadenopathy, prior injection of B cells had virtually no effect in promoting LN priming. In marked contrast, injection of B cells into mice exhibiting less-pronounced LN enlargement (mice tested at 14 to 16 wk) was highly effective in restoring LN priming; before B cell injection, the LN of these mice contained only 2 to 5% B cells. These findings add to the evidence that T cell priming in LN is heavily dependent on the presence of B cells.

Adjuvants, Immunologic↗
PubMed1987

Variable capacity of L3T4+ T cells to cause lethal graft-versus-host disease across minor histocompatibility barriers in mice.

Highly purified populations of L3T4+ and Lyt-2+ T cell subsets were compared for their capacity to cause lethal GVHD in six different H-2-compatible, multiple minor histocompatibility antigen-different murine strain combinations. In four of these combinations (C3H.SW----B6, DBA/2----B10.D2, B10.BR----CBA, and B10.S----SJL), lethal GVHD appeared to be caused almost entirely by Lyt-2+ cells; the injection of L3T4+ cells resulted in low mortality even when these cells were presensitized to the recipient antigens. In the remaining two combinations (B10.D2----DBA/2 and B10.D2----BALB/c), L3T4+ T cells were able to cause a high incidence of GVHD and were more potent than the Lyt-2+ cells. The implications of these findings are discussed.

Animals↗
PubMed1987

T cell priming in vivo: a major role for B cells in presenting antigen to T cells in lymph nodes.

Previous studies have shown that lymph node (LN) T cells from mice given repeated injections of anti-mu antisera from birth (mu sm) fail to mount secondary T proliferative responses to antigen in vitro after s.c. priming in vivo. This finding raised the possibility that priming of T cells in LN depends on the presence of B cells, Ig+ B lymphocytes being absent in mu sm. In support of this idea, the present paper shows that the priming defect in LN of mu sm can be largely overcome by injecting B cell populations s.c. 1 day before s.c. priming with antigen. Restoration of LN priming was observed with s.c. injection of highly purified populations of small B cells but not with heat-killed or lightly irradiated B cells. Homing studies indicated that approximately 10% of s.c.-injected B cells reached the draining LN. In other studies, irradiated mice injected i.v. with purified T cells manifested poor priming in LN after s.c. injection of antigen. It was reasoned that the LN priming defect in this situation reflected the lack of B cells in irradiated mice, B cells being highly radiosensitive. In support of this notion, it was found that s.c. injection of B cells into irradiated recipients of T cells led to high priming of T cells in LN after s.c. injection of antigen. Although T cells exposed to antigen in B-depleted LN of mu sm and irradiated mice gave negligible T proliferative responses in vitro, low but significant levels of primed T helper function were detected in a sensitive T helper assay in vivo. In light of this finding, our working hypothesis is that the initial induction of T cells to antigen in LN is controlled by resident dendritic cells (or other non-B antigen-presenting cells), the main role of B cells being to control the clonal expansion of activated T cells.

Animals↗
PubMed1987

Downregulation of T cell responses by antibodies to the T cell receptor.

We have derived a T cell clone that recognizes and responds to three different types of antigen: self + X (fowl gamma globulin + H-2d), allo-H-2p,b, and minor lymphocyte-stimulating (Mlsa,d) determinants. Anti-TcR mAb and their F(ab')2 and Fab fragments were tested for their capacity to block the response of this clone. When responses were assayed on day 4 or later, addition of KJ16 or F23.1 mAb caused a marked inhibition of the response to each of the three antigens recognized by the clone. Responses measured at earlier time points however were unaffected or enhanced. This finding suggested that the inhibitory effects of anti-TcR mAb that followed the phase of enhancement might have reflected downregulation of the cells rather than simple blockade of TcR. In support of this possibility it was found that addition of anti-TcR mAb caused marked inhibition of the response of the clone to IL-2, i.e., a response that is not known to involve the TcR.

Animals↗
PubMed1986

T cell specificity in twice-irradiated F1----parent bone marrow chimeras: failure to detect a role for immigrant marrow-derived cells in imprinting intrathymic H-2 restriction.

In an attempt to resolve the issue of whether H-2-restricted T cell specificity is controlled by thymic epithelial cells or by cells of the macrophage/dendritic cell (M phi/DC) lineages, long-term F1----parent chimeras were subjected to secondary irradiation and reconstitution with F1 marrow cells. The rationale was that if F1 M phi/DC enter the thymus only quite slowly after irradiation, as claimed by other investigators, leaving F1----parent chimeras for a period of several months before re-irradiation would ensure that the new wave of T cells generated in the thymus of the chimeras would have no difficulty in making contact with donor-derived F1 M phi/DC. According to the view that M phi/DC rather than epithelial cells control H-2 restriction, the T cells differentiating in these chimeras would be expected to show H-2 restriction to both parental strains. In practice, T cells from twice-irradiated (1000 + 800 rad) chimeras showed strong restriction to host (thymic) H-2 determinants, the degree of restriction to host determinants being as marked as with T cells from once-irradiated chimeras. This finding applied both to T proliferative responses to KLH assayed in vitro and to T helper function for sheep erythrocytes measured in vivo. Preliminary experiments established that the initial dose of irradiation used for preparing the chimeras (1000 rad) resulted in almost total replacement of intrathymic M phi/DC by donor-derived cells within 4 wk of irradiation; M phi/DC were typed by determining their capacity to stimulate mixed-lymphocyte reactions. Collectively, the data imply that, at least under the conditions used, H-2-restricted T cell specificity is controlled by epithelial cells rather than by M phi/DC.

Animals↗
PubMed1986

Exogenous control of I-A expression in fetal thymus explants.

With the use of a system in which 14 day fetal thymus lobes were cultured in vitro with bone marrow or other lymphoid cells, evidence was obtained that entry of macrophage/dendritic cells (M phi/DC) into the thymus causes a marked rise in the density of endogenous I-A molecules expressed in the cortex, presumably on epithelial cells. High cortical I-A expression also occurred when thymus lobes were cultured with supernatants containing IFN-gamma; addition of anti-IFN-gamma antibody blocked I-A induction. The working hypothesis for these findings is that cellular interactions occurring in the medullary region between M phi/DC and a subset of thymocytes leads to production of IFN-gamma, which then diffuses into the cortex and promotes epithelial I-A expression. The possible relevance of this scheme to the process of thymic "education" is discussed.

Animals↗
PubMed1986

Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences.

Highly purified populations of C57BL/6 (B6) L3T4+ and Lyt-2+ T cell subsets were compared for their capacity to exert alloreactivity to class I vs. class II H-2 differences in vivo. B6 Lyt-2+ cells responded strongly to the class I different mutant, bm1, as manifested by DNA synthesis in the spleen of irradiated mice followed by entry of blast cells into thoracic duct lymph, induction of splenomegaly in newborn mice, production of lethal GVHD in irradiated mice, and skin allograft rejection. By all of these parameters, B6 Lyt-2+ cells showed almost total unresponsiveness to the class II-different mutant, bm12. Reciprocal results were observed with B6 L3T4+ cells, these cells responding strongly against bm12 but not against bm1. In the case of purified T cell subsets from other strains, CBA/Ca and B10.BR L3T4+ cells both responded well to a full H-2 difference. Responses by Lyt-2+ cells from these strains were weaker, especially for CBA/Ca cells. The implications of these findings are discussed.

Animals↗
PubMed1986

Functions of purified L3T4+ and Lyt-2+ cells in vitro and in vivo.

The expression of L3T4 and Lyt-2 cell surface molecules separates T cells into two broad, non-overlapping subsets: typical T helper cells are L3T4+ Lyt-2- whereas most T killer cells and their precursors are L3T4- Lyt-2+. This review compares highly purified populations of unprimed L3T4+ and Lyt-2+ cells for their capacity to respond to class I vs. class II H-2 alloantigens. Various parameters are considered, including generation of mixed lymphocyte reactions (MLR) and cell mediated lympholysis (CML) in vitro, proliferative responses in irradiated mice, graft-versus-host reactions and skin allograft rejection. In all of these assays the two T cell subsets exhibit marked specificity in their response to H-2 alloantigens, L3T4+ cells responding only to class II and not class I differences and Lyt-2+ cells showing reciprocal specificity. Contrary to current dogma, the bulk of the evidence suggests that primary responses of Lyt-2+ cells do not depend on exogenous help provided by other T cells.

Animals↗
PubMed1985

Properties of purified T cell subsets. I. In vitro responses to class I vs. class II H-2 alloantigens.

In light of the widely accepted view that Ia-restricted L3T4+ T helper cells play a decisive role in controlling the differentiation of Lyt-2+ cells, experiments were designed to examine whether Lyt-2+ cells can respond to antigen in the absence of L3T4+ cells. The results showed that highly purified Lyt-2+ cells gave high primary mixed lymphocyte reactions (MLR) to various class I differences, including both mutant and allelic differences; responses to class II (Ia) differences were generally undetectable with Lyt-2+ cells. The intensity of MLR to class I differences was not affected by addition of anti-L3T4 monoclonal antibodies (mAb) to the cultures or by removing T cells from the stimulator populations. Negative selection experiments showed that Lyt-2+ cells could respond to class I differences across Ia barriers. MLR of purified Lyt-2+ cells peaked on days 3-4 and then fell sharply; background responses with syngeneic stimulators (auto-MLR) were virtually absent. Parallel experiments with purified L3T4+ cells showed that this subset responded in MLR only to class II (Ia) and not class I differences, reached peak responses only on day 6 rather than days 3-4, and often gave high auto-MLR. Within the first 3-4 d of culture, MLR were generally higher with Lyt-2+ cells than L3T4+ cells. Although no evidence could be found that Ia-restricted L3T4+ cells were required for the response of Lyt-2+ cells, presentation of antigen by Ia+ cells appeared to be essential. Thus, responses were ablated by pretreating stimulator cells with anti-Ia mAb plus C'. Significantly the failure of Lyt-2+ cells to respond to anti-Ia plus C'-treated stimulators could not be restored by adding syngeneic spleen cells; addition of IL-2 led to only a minor (15%) restoration of the response. It is suggested that Ia+ cells provide an obligatory second signal required by Lyt-2+ cells.

Animals↗
PubMed1985

Prolonged survival in vivo of unprimed B cells responsive to a T-independent antigen.

Despite earlier evidence to the contrary, it has recently been claimed that most B lymphocytes, including lymph node (LN) and thoracic duct B cells, are short-lived cells of recent marrow origin. To seek direct information on this question, we transferred unprimed LN or thoracic duct B cells from normal mice to xid mice, i.e., mice unresponsive to the T-independent antigen, trinitrophenyl (TNP)-Ficoll. At varying periods after B cell transfer the recipients were challenged with TNP-Ficoll; anti-TNP plaque-forming cells were assayed in the spleen 6 d later. The results showed that the B cell recipients retained responsiveness to TNP-Ficoll for at least 3 mo after transfer. Responsiveness increased within the first 3 wk but then remained relatively constant. These findings imply that, at least for TNP-Ficoll-reactive cells, B cells residing in LN and thoracic duct lymph are not short-lived cells of recent marrow. Indeed, the data suggest that once the pool of recirculating B cells is fully formed in adult mice, further input of newly formed cells from the marrow into the recirculating pool is very limited.

Animals↗
PubMed1985

T cell receptors for responses to Mls determinants and allo-H-2 determinants appear to be encoded on different chromosomes.

Previous studies have shown that T cell clones specific for strong Mlsa,d determinants concomitantly display apparently random reactivity to allo-H-2 determinants. One explanation for this finding is that T cell recognition of Mlsa,d and allo-H-2 determinants is controlled by separate sets of receptors. If these receptors were chromosomally unlinked, karyotypically unstable T cell hybrids with dual reactivity for Mlsa,d and particular allo-H-2 determinants would be expected, occasionally, to lose reactivity for one set of determinants, but not the other. The results presented here provide direct support for this prediction.

Animals↗