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ABSTRACT: In this study the role of the thymus in the development of sessile T cell populations resident in spleen and lymph nodes (LN) was contrasted with the development of recirculating T cell populations trafficking between blood and lymph. Extensive analysis of the composition and the rate of growth of the secondary lymphoid tissues and recirculating lymphocyte pool coupled with neonatal thymectomy revealed that the sessile and recirculating T cell populations showed different degrees of thymic dependency and increased in size at different rates, suggesting these two populations might be under separate homeostatic control. Neonatal thymectomy also resulted in a much greater depletion of CD8+ and gammadelta TCR+ T cell subsets compared with CD4+ T cells in the sessile and recirculating T cell pools, and greatly reduced the number of T cells homing to peripheral lymph nodes compared with those homing to the gut.
International Immunology 12/2001; 13(11):1351-9. · 3.41 Impact Factor
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R G Windon,
P J Chaplin,
P McWaters,
M Tavarnesi,
M Tzatzaris,
W G Kimpton, R N Cahill,
L Beezum,
A Coulter,
D Drane,
A Sjölander,
M Pearse,
J P Scheerlinck,
J M Tennent
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ABSTRACT: The peripheral (draining) lymph node, as the primary site of immune induction, determines the course of systemic responses to an injected antigen. Lymphatic duct cannulation procedures in sheep were used to investigate local immunoreactivity to human influenza virus antigen (Flu ag) admixed with the adjuvant ISCOMATRIX (IMX). Compared to Flu ag or IMX alone, the co-administration of Flu ag and IMX (Flu ag+IMX) synergistically enhanced a number of immunological responses (lymphocyte and blast migration from the node, antigen-specific antibody levels and IL6 output in efferent lymph, and antigen-induced proliferation in cultured efferent lymph cells). Together, these results demonstrate that IMX is an immune modulator, and that lymphatic duct cannulation procedures may be used to evaluate antigen/adjuvant combinations for vaccine development.
Vaccine 12/2001; 20(3-4):490-7. · 3.77 Impact Factor
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ABSTRACT: A diverse repertoire among peripheral T cells is established in early life by thymic export when the naive T cell pool is first formed. In contrast, during adult life the thymus has been thought to play only a minor role in T cell homeostasis. As individuals age there is an increasing proportion of peripheral T cells bearing a memory phenotype, as well as a corresponding decrease in the number of naive T cells. The change in the composition of the peripheral T cell pool with age is thought to occur as a result of reduced or completely curtailed thymic export following thymic involution at puberty together with the antigen-driven expansion of naive T cells in the periphery. We examined thymic export throughout life in fetal, neonatal and aged sheep. We found that the thymus in adult animals showed an efficiency of production and export on a per gram basis equivalent to that observed for much younger animals, and continued to export substantial numbers of T cells long after puberty. The data demonstrate that naive T cells constantly enter the peripheral T cell pool at the same rate throughout fetal, neonatal and adult life, and that one in every 50 T cells in the peripheral lymphoid tissues of aged sheep had emigrated from the thymus in the previous 24 h. The data suggest that restoration by the thymus of a normal peripheral T cell repertoire in chronic T cell-depleting conditions should be possible in adult patients, provided the thymus is not damaged by disease or therapy.
European Journal of Immunology 04/2001; 31(3):802-11. · 5.10 Impact Factor
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ABSTRACT: Before parturition the fetal lamb develops a large pool of long-lived recirculating T cells which provides a large population of naive T cells with a diverse TcR repertoire. After birth and concomitant with exposure to environment antigens, fetal T cells are rapidly replaced by short-lived cells formed postnatally. The majority of thymic emigrants homing to spleen in postnatal lambs are short-lived, in contrast to emigrants targeting lymph nodes where a population appears to be long-lived. The lifespan of thymic emigrants in the fetus is unknown as in the relative importance of antigen-driven processes versus developmental programming in regulating T cell homeostasis in early postnatal life.
Veterinary Immunology and Immunopathology 12/1999; 72(1-2):175-81. · 2.08 Impact Factor
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ABSTRACT: We have studied the appearance and phenotype of recent thymic emigrants in blood, spleen and lymph nodes (LN) of neonatal lambs. Using in situ labelling of thymocytes with fluoroscein isothiocyanate (FITC), we examined the expression of the LN homing receptor L-selectin on alphabeta and gammadelta subsets of recent thymic emigrants 24 hr after labelling. There were marked differences in the proportions of CD4+, CD8+ and gammadelta T-cell receptor (TCR+) cells exported from the thymus to spleen compared to lymph nodes. Spleen was enriched in CD8+ and gammadelta TCR+ emigrants while LN were enriched in CD4+ emigrants. There were also marked differences in the expression of L-selectin by emigrants homing to spleen compared with those homing to lymph nodes. While the majority of thymic emigrants in LN expressed L-selectin, considerably fewer emigrants in spleen were L-selectin+. The presence of large numbers of CD8+ L-selectin- and gammadelta TCR+ L-selectin- thymic emigrants homing to spleen raises the possibility that unique homing receptor specificities underpin the migration of T cells to spleen as distinct from lymph nodes.
Immunology 12/1999; 98(3):422-6. · 3.32 Impact Factor
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ABSTRACT: Studies on the ontogeny of the immune system in the sheep foetus, which remains immunologically naive until after birth, indicate that a large scale recirculation of T cells is just as much a feature of the foetal immune system as it is in animals after birth. An extensive recirculation of T cells and dendritic cells through peripheral tissues-including the gastrointestinal tract and skin-develops early in foetal life, although a population of gut-homing memory T cells does not develop until postnatal life. Current evidence suggests that two populations of thymic emigrants with distinct tissue-homing specificities to spleen and lymph node contribute to the development of the foetal peripheral T cell pool. CD8(+) thymic emigrants mostly target spleen while CD4(+) thymic emigrants home predominantly to lymph nodes. The lifespan of thymic emigrants is uncertain, although cells entering lymph are long-lived and form the basis of a diverse pre-immune repertoire of recirculating T cells. The life history and growth rates of non-recirculating T cells in spleen and lymph nodes during foetal life are at present unknown.
Seminars in Immunology 05/1999; 11(2):105-14. · 6.39 Impact Factor
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ABSTRACT: Lymphocyte recirculation is an essential element in the integration of immune responses and is an absolute requirement for the development of systemic memory in postnatal animals. During foetal life a large pool of recirculating T cells develops and migration pathways of naive T cells to skin and peripheral tissues as well as LN are established. At birth a process is triggered whereby naive fetal T cells are rapidly lost from the circulating pool and are replaced by newly arriving T cells which have been formed since birth. At present our data suggest that the thymic export in the fetus creates a pool of long-lived naive T cells of wide diversity. The situation in neonatal lambs is more complex since the thymus is exporting large numbers of short-lived thymic emigrants which enter a peripheral T-cell population where many T cells are dividing.
Seminars in Immunology 01/1998; 9(6):355-63. · 6.39 Impact Factor
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ABSTRACT: Lymphocyte recirculation is critical to maximize the efficiency of immunological surveillance and is an absolute requirement for the development of systemic memory. The consensus view of the lifespan of peripheral T cells holds that naive T cells are long-lived cells and most memory T cells are short-lived cells, although the question of the lifespan of peripheral T cells is not yet fully resolved. We have studied the lifespan of T cells circulating in efferent lymph draining lymph nodes (LN) in the immunologically naive sheep fetus and in postnatal lambs immediately following birth by examining the in vivo incorporation of [3H]thymidine by newly formed T cells during continuous administration of [3H]thymidine. We report that authentically naive fetal T cells are long-lived cells which continue to recirculate between blood and lymph during fetal life. At birth, however, a process is triggered whereby fetal T cells circulating through LN are rapidly lost from the peripheral T cell pool and are replaced by freshly arriving T cells which have been formed since birth. Our results indicate that by the end of the first week of postnatal life, around three-quarters of the T cells circulating through peripheral LN have been formed since birth.
International Immunology 10/1997; 9(9):1253-8. · 3.41 Impact Factor
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ABSTRACT: Ruminant gamma delta T cells are concentrated at epithelial surfaces and share many features in common with species such as mice and humans which contain relatively fewer gamma delta T cells than ruminants. To date no gamma delta T cells with invariant TcR have been found in sheep and the generation of gamma delta TcR diversity which is thymic dependent follows a developmentally regulated sequence. Analysis of thymic export of gamma delta T cells shows that emigration of gamma delta T-cell subsets increases markedly during fetal life and after birth suggesting intrathymic processes leading to mature gamma delta T cells may change during development. Skin homing gamma delta T cells acquire their tissue tropism inside the thymus and pathways of recirculation of gamma delta T cells to skin are laid down during fetal development independent of antigen and remain stable through into adult life.
Seminars in Immunology 01/1997; 8(6):351-60. · 6.39 Impact Factor
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ABSTRACT: Tissue-specific circulation of T cells is a critical element in the integration of systemic immune responses. Current models of T-cell migration suggest that homing specificities of T cells for tissues such as gut and skin are generated outside the thymus as a result of activation of virgin T cells by antigen in lymph nodes. We have used the sheep fetus (which is immunologically virgin and contains no memory or effector T-cell subsets) to examine the migration of 51Cr-labelled T cells in vivo. We report that gut-homing T cells are not present in the fetus and that gut-homing T cells from postnatal lambs home normally to fetal gut. Fetal thymectomy performed immediately prior to birth failed to prevent the development of gut-homing T cells in postnatal life. Gut-homing specificities on T cells are thus acquired extrathymically.
Immunology 06/1996; 88(1):130-3. · 3.32 Impact Factor
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ABSTRACT: Current models of T cell migration place severe restrictions on the recirculation of virgin T cells, condemning them to migrate exclusively via high endothelial venules in lymph nodes until they either die or acquire the capacity to migrate to skin and peripheral tissues as memory cells following stimulation with antigen. We have demonstrated in the sheep fetus (which is immunologically virgin until after birth) that virgin T cells and dendritic cells circulate through skin and peripheral tissues during fetal life in the same non-random manner as adult T cells but in much larger numbers than they do in adult animals. Our data also showed that T cells do not discriminate between peripheral tissues and skin or lymph nodes on the basis of virgin or memory CD45R phenotype, or CD2, CD58 or CD44 phenotype, and with the possible exception of CD11a/CD18, that it is not mandatory for lymphocytes to be activated to adhesion moleculehi status in order to home to fetal skin. Our results indicate that unique tissue-homing specificities for extra-lymphoid tissues can be imprinted on virgin T cells independent of foreign antigen. Virgin T cells have previously been thought to be denied access to peripheral tissues; however, the large-scale traffic of virgin T cells through extra-lymphoid tissues in the fetus reported here provides a mechanism whereby direct virgin T cell interactions with self-antigens expressed only on tissues outside the thymus can occur repeatedly during development of the fetal immune system.
International Immunology 11/1995; 7(10):1567-77. · 3.41 Impact Factor
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ABSTRACT: Current models of lymphocyte traffic suggest that homing specificities of T cells to tissues such as skin are generated outside the thymus as a result of activation of naive T cells by antigen in lymph nodes. Virgin T cells are thought to home to high endothelial venules in lymph nodes, but are thought to be unable to home to extra-lymphoid tissues such as skin. We used the technique of in situ labeling of the thymus with fluorescein isothiocyanate to examine the homing specificities of authentically naive T cells in vivo, immediately after their export from the thymus. We report that homing specificities for skin as well as lymph node are imprinted on T cells inside the thymus, independent of antigen. We also show that both alpha beta and gamma delta emigrant T cells exhibit homing patterns to skin and lymph nodes which are identical to those of mature T cells. Our findings demonstrate a key role for the thymus in the induction of skin-homing specificities on T cells indicating that skin-homing specificities of T cells are not generated solely outside the thymus as a result of the activation of virgin T cells by antigen. The migration of thymic emigrants to extra-lymphoid tissues within a few hours of leaving the thymus may have implications for mechanisms of peripheral self-tolerance. This pathway provides an opportunity for direct virgin T cell interactions with self components only expressed in the periphery at a time when emigrants may be more susceptible to tolerance induction than mature circulating T cells.
European Journal of Immunology 04/1995; 25(3):723-7. · 5.10 Impact Factor
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ABSTRACT: We have compared the expression of CD2, CD11a/CD18, CD44, and CD58 and alpha beta and gamma delta T cells emigrating from the fetal and postnatal thymus. We report that both gamma delta and the CD4+CD8- and CD4-CD8+ subsets of alpha beta T cells express mature levels of the adhesion molecules CD11a/CD18, CD44, and CD58 upon emigration from the thymus. Whereas CD44 is up-regulated on gamma delta + thymocytes prior to export, down-regulation of both CD11a/CD18 and CD58 occurs prior to emigration from the thymus, suggesting that down-regulation of these molecules may be a final maturational step taken by developing gamma delta T cells before their export from the thymus. In contrast, there is continued up-regulation of CD2 on gamma delta and alpha beta T cells upon emigration from the thymus and as they move into the mature peripheral T-cell pool. There was also a marked reduction in the number of CD2+ gamma delta T cells exported during fetal development that was associated with a marked reduction in the percentage of CD2+ gamma delta thymocytes exported. The postthymic maturation of CD2 and the other changes in adhesion-molecule expression appear to be independent of extrinsic antigen, as the same changes were observed in the antigen-free environment of the fetus as in the postnatal lamb, which has been exposed to extrinsic antigen. It thus appears that these changes in adhesion-molecule expression are as a result of the normal maturation pathway from a developing thymocyte to a mature peripheral T cell.
Developmental Immunology 02/1995; 4(3):199-209.
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ABSTRACT: Tissue-selective streaming of T cells is considered to be a critical element in the integration of normal immune responses in intact animals. The results presented in this paper show that while there were major subsets of gut-homing T cells present in intestinal lymph, there were considerable differences in the tissue tropism of T cell populations circulating in lymph draining gut and peripheral lymph nodes. Thus, while CD4+ cells returned preferentially to their tissue of origin, gamma delta T cells showed a strong migratory preference for peripheral lymph nodes regardless of their tissue of origin. In contrast, although a population of gut-homing CD8+ cells was present in ileal lymph, CD8+ T cells from peripheral lymph nodes homed equally well to gut and lymph nodes. There were also considerable differences in the expression of L-selectin on T cells circulating in the two compartments. L-selectin was down-regulated on alpha beta T cells present in ileal lymph but not on gamma delta T cells which expressed the highest levels of L-selectin of all T cell subsets. It is suggested that gut-homing alpha beta T cells which have down-regulated L-selectin are formed in the gut-associated lymphoid tissues in response to gut antigens while the migratory properties of gamma delta T cells are ontogenetically determined, independent of antigen.
International Immunology 01/1995; 6(12):1891-7. · 3.41 Impact Factor
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ABSTRACT: The thymus plays an essential role in the generation and selection of T cells and exports approximately 0.5-1% of thymocytes per day in young animals and considerably fewer in older animals. To date there have been no studies directly examining fetal thymic export in any species. Using the technique of intrathymic injection of fluorescein isothiocyanate, followed by an assay for green fluorescent cells in the periphery and for the expression of cell surface antigens on these cells, we have compared directly the export of T cells from the fetal and postnatal ovine thymus. While the thymus exports both alpha beta and gamma delta T cells, our results demonstrate that the proportion of thymic gamma delta T cells that are exported per day is much higher than that of thymic alpha beta T cells. Moreover, the export rate of gamma delta T cells increased from approximately 1 in every 60 gamma delta thymocytes per day emigrating from the fetal thymus to 1 in every 20 from the postnatal thymus. In addition, we identify a population of CD5+CD4-CD8-gamma delta-. T cells emigrating from the fetal thymus but greatly reduced among thymic emigrants after birth. These findings have several implications regarding the mechanisms and control of selection of both gamma delta and alpha beta T cells.
European Journal of Immunology 11/1994; 24(10):2329-36. · 5.10 Impact Factor
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ABSTRACT: We have used the technique of in situ intrathymic injection of fluorescein isothiocyanate to examine L-selectin expression on gamma delta and alpha beta T cells immediately after emigrating from the thymus of fetal and postnatal animals. We found that the percentage of L-selectin+ thymocytes exported per day decreased by half after birth and that the export of T cells from the thymus does not rely on expression of the peripheral lymph node homing receptor, L-selectin. Analysis of L-selectin on emigrant and mature T cell subsets revealed a remarkable heterogeneity of expression, both in terms of the numbers of cells expressing this molecule as well as the level of expression. gamma delta T cells, reportedly not having a propensity for homing to lymph nodes, not only contained the highest proportion of L-selectin+ cells, but also expressed far more of this molecule than either CD4+CD8- or CD4-CD8+ alpha beta T cells. Furthermore, those emigrant T cells expressing L-selectin are somewhat immature in their expression of this molecule. Subsequent maturation resulted in up-regulation of L-selectin on mature peripheral blood T cells, maturation that was clearly independent of extrinsic antigen. This antigen-independent post-thymic maturation appeared to occur as part of the normal progression from immature thymocyte to mature peripheral T cell in both fetal and postnatal animals.
European Journal of Immunology 06/1994; 24(5):1234-9. · 5.10 Impact Factor
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Australian and New Zealand journal of medicine 03/1994; 24(1):71.
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ABSTRACT: We have compared the expression of CD45RA on alpha beta and gamma delta T cells emigrating from the fetal and postnatal thymus. The fetal and postnatal thymus export both CD45RA+ and CD45RA- T cells. The number of gamma delta +CD45RA+ T cells was remarkably constant regardless of stage of ontogeny or T cell maturity. Around 5-8% of gamma delta thymic emigrants, thymocytes and peripheral blood lymphocytes expressed CD45RA in both fetal and postnatal animals. In contrast to gamma delta T cells, up to one quarter of both fetal and postnatal alpha beta emigrants expressed CD45RA. Post-thymic maturation of CD45RA expression of alpha beta emigrants, which occurred both before and after birth, appeared to be antigen independent.
European Journal of Immunology 02/1994; 24(1):186-90. · 5.10 Impact Factor
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ABSTRACT: The metabolic half-life of hyaluronan (HA) in synovial fluid was estimated in sheep from the rate of appearance of 3H2O in plasma after injection of highly polymerized labeled HA. This material is substituted with 3H in its acetyl group and is rapidly and almost completely degraded in sheep and other species to yield 3H2O. Previously sensitized sheep were studied before and after induction of acute monoarticular arthritis by intraarticular challenge with type II collagen. In both circumstances 3H was released from the joint in a monophasic exponential pattern and appeared in plasma only as 3H2O. Before challenge, the mean metabolic half-life of [3H]HA was 20.8 hours (range, 15.8 to 27.9 hours, n = 5); an estimate in a single unsensitized sheep (27.0 hours) fell within this range. After challenge, swelling occurred around the joint without frankly increased synovial fluid. The mean half-life fell to 11.5 hours (range, 9.0 to 16.8 hours), with a corresponding increase in mean fractional turnover from 3.5%/h to 6.3%/h; an increased amount of the label was also retained within the peripheral tissues. It is concluded that a relatively mild acute inflammation can induce major changes in the metabolic turnover of synovial HA without the development of gross effusions. In the course of this study, mean synovial fluid volume in the normal sheep hock joint was estimated to be 1.54 mL; the concentration and content of HA were 0.54 mg/mL and 0.84 mg, respectively. These data add to other evidence that the volume and HA content of normal synovial fluid vary widely in different joints and species.(ABSTRACT TRUNCATED AT 250 WORDS)
Seminars in Arthritis and Rheumatism 07/1993; 22(6 Suppl 1):9-17. · 4.97 Impact Factor
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ABSTRACT: Tissue-specific and lymphocyte subset-specific lymphocyte recirculation patterns have been analysed simultaneously. Lymphocytes obtained from one lymph compartment were directly labelled with fluorochrome in vitro and returned to the blood of the same animal. Over the next 48-72 h, the recirculation of these cells into both the same lymph compartment and at least one different lymph compartment was monitored. The cells in all of these lymph collections, as well as an aliquot of the cells used for direct fluorescent labelling, were then phenotyped with monoclonal antibodies (mAb) which define the mutually exclusive small CD4+ and CD8+ T-lymphocyte subsets in sheep. All cell samples were analysed by flow cytometry and CD4/CD8 ratios were determined for the recirculated, fluorochrome-labelled population in each lymph collection. The mean CD4/CD8 ratio calculated for each lymph compartment was then compared with the CD4/CD8 ratio calculated for each lymph compartment was then compared with the CD4/CD8 ratio of the transfused, starting population. In one experiment employing efferent prescapular lymph cells, three experiments employing efferent intestinal lymph cells, and two experiments employing afferent intestinal lymph cells, tissue-specific recirculation was observed. In all of these experiments, the pattern of recirculation of small CD4+ and CD8+ T lymphocytes was non-random. Moreover, in each experiment, this non-randomness was completely unrelated to tissue-specific phenomena, since the mean CD4/CD8 ratio of the recirculated population was higher than the CD4/CD8 ratio of the transfused, starting population regardless of the lymph compartment examined. These data are therefore consistent with the hypothesis that tissue-specific and lymphocyte subset-specific lymphocyte-endothelial cell recognition mechanisms independently direct the recirculation of small lymphocytes from blood to lymph.
Immunology 03/1991; 72(2):239-45. · 3.32 Impact Factor
