The mechanisms governing migration and extramedullary dissemination of leukemic cells remain obscure. In this study the migration and in vivo homing to the bone marrow of nonobese diabetic severe combined immunodeficient (NOD/SCID) mice injected with human precursor-B acute lymphoblastic leukemia (ALL) cells in comparison to normal CD34+ progenitors (both cord blood and mobilized peripheral blood) was investigated. Although migration and homing of both cell populations was dependent on stromal cell-derived factor 1 (SDF-1)/CXCR4 interactions, major differences in receptor expression as well as the migratory capacity toward various concentrations of SDF-1 were found. Furthermore, unlike normal CD34+ progenitors, in vivo homing of the leukemic cells was superior when recipient NOD/SCID mice were not irradiated prior to transplantation. In addition, we report differences in the adhesion molecules activated following SDF-1 stimulation, documenting a major role for very late antigen 4 (VLA-4), but not VLA-5 and lymphocyte function-associated antigen-1 (LFA-1), in homing of precursor-B ALL cells. Interestingly, Toxin-B and pertussis toxin inhibited the homing of the leukemic cells but not that of normal CD34+ progenitors or normal CD10+/CD19+ precursor-B cells, revealing differences in CXCR4 signaling pathways that are based on changes that acquired by the leukemic cells. Altogether, our data provide new insights into different SDF-1-induced signaling, activation, and consequent motility between normal CD34+ and precursor-B ALL progenitors, which may lead to improved clinical protocols.

The possibility that mature lymphocytes play a role in the regulation of human T cell development was studied in the experimental model of fetal thymus organ cultures (FTOC), by reconstituting lymphocyte-depleted murine fetal thymus (FT) lobe with cells isolated from human umbilical cord blood (CB). Cultures were incubated with human cytokines (IL-7, FLT-3 ligand and Steel Factor), or remained untreated. When CD4+, or CD8+ CB cells, were co-cultured with FT explants, they expanded and maintained their original phenotypic markers, with no significant effect of the cytokines. Cultures of human hematopoietic stem cells (CD34+) gave rise to CD4+CD8− cells, which were mainly CD3−, with no indication of further intermediate developmental stages. However, a limited number of CD4+CD8+ (double positive [DP]) cells were detected when the CD34+ cells were co-cultured with CD4+ cells from the same CB samples. In contrast, FT with unseparated CB cells resulted in the different CD4/CD8 subsets, and their numbers increased in the presence of cytokines. The appearance of DP cells depended on the presence of either CD4+ or CD8+ cells in the cultured CB samples. Hence, DP cells were not detected when the CB was depleted of CD4+ and CD8+ cells (“depCB”) before culture, and they appeared when depCB were co-cultured with either CD4+ or CD8+ cells. In contrast, CD4+ cells inhibited the development of CD8+CD3+ cells, and this was most pronounced in the absence of the cytokines. There was no symmetrical down-regulatory effect of CD8+ cells on the development of CD4+CD3+ cells. Addition of IL-15 to the cytokine mixture led to an increased proportion of CD56+ cells in cultures of CD34+ cells. The presence of CD4+, and not CD8+ cells, interfered with this process. Our results thus imply differential effects of CD4+ and CD8+ cells on thymocytopoiesis.

Influenza infections may cause serious morbidity, as well as mortality in the elderly. In the present study we vaccinated old and young mice of two strains with three synthetic recombinant constructs (Levi and Arnon, 1995. In: Chanock, R.M. et al. (Eds.), Vaccines 95. CSHL Press, New York, pp. 311–316) and examined their capacity to eliminate a challenge of virus. Virus clearance from the lungs in the aged was very efficient, although the immune response in the aged was comparatively reduced. The data demonstrate that an intranasal administration of peptide-based anti-influenza vaccine without any adjuvant can be efficient and protective in old mice. Further studies are needed to determine whether such constructs will provide an effective vaccine for elderly human subjects.

The study was designed to establish whether the ability to rearrange the T cell receptor (TCR) Vbeta genes is altered with age. We examined the expression of recombinase activating genes, RAG-1 and RAG-2, in the thymus of mice at different ages (2-24 months). A significant age-related decrease in RAG-1 and RAG-2 expression was observed in the thymocytes from the age of 12 months and over. To find out if this decrease is determined in the thymocyte progenitors or induced by the thymic microenvironment, we co-cultured lymphoid depleted fetal thymus (FT) explants with bone marrow cells, or immature thymocytes, from young and old mice. The developing thymocytes were examined at different time intervals during the first week of culture. Whereas cells derived from the immature thymocytes of the old donors failed to express RAG-1 and RAG-2, compared to the young, the bone marrow derived cells of both age groups did show this expression, and there was no difference in Vbeta rearrangement of the TCR. Our study indicates that T cell progenitors in the aging bone marrow retain the potential to give rise to T cells with TCR rearrangements, and the expression is determined by the thymic stroma.

The expression of estrogen receptor (ER) in thymocytes was studied in young, middle-aged, and old (2, 12, and 24 months, respectively) female and male C57BL/6J mice. Western immunoblots prepared from the thymocytes of females of all age groups showed the presence of a 67-kD protein band, which has been associated with the apparent MW of denatured ER. Flow cytometry analysis o,f cells stained with a monoclonal anti-ER antibody (clone 13H2) disclosed ER expression in both females and males of all age groups. In vivo treatment with estradiol (E 2 ) led to an increase in the specific activity of thymic creatine kinase (CK) in the female mice, whereas the male thymocytes responded with an increase in CK activity only on treatment with dihydrotestosterone (DHT). The data show no differences in ER expression between male and females, but the receptor appears not to be functional in males. Interestingly, when estradiol was applied to co-cultures of lymphoid-depleted fetal thymus (FT) explants and bone-marrow cells, or thymocytes, from young and old females, it resulted in increased cellularity of cultures containing cells of the young, and not those of the old. The proportion of CD4/CD8 phenotypes of the developing cells in these cultures was not affected by E 2 treatment. These observations provide a new insight into ER expression and function in T-cell development in relation to gender and age.

Dysfunction of T lymphocytes in aging has been causally related to a gradual loss of the thymic microenvironmental function. However, in view of the fact that T cells are generated from bone marrow-derived stem cells that settle in the thymus, we have investigated the possibility that aging effects on the bone marrow have an impact on T cell development. Our approach was based on seeding of bone marrow cells, from young and old mice, onto lymphoid-depleted fetal thymus explants, and examining the patterns of T lymphocyte development under organ culture conditions. The results indicate multifactorial effects of aging, on pre-thymic and intra-thymic developmental processes, as well as on feedback regulation by mature T cells.

Effects of mature T lymphocytes on thymic colonization by lymphohemopoietic cells were investigated in an in vitro experimental model, using a variety of experimental strategies. Lymphoid-depleted fetal thymus (FT) explants (C57BL/Ka, Thy1.1, H-2(b)) were incubated with bone mallow (BM) cells from syngeneic (C57BL/Ka; SBM) and allogeneic (BALB/c, Thy1.2, H-2(d); ABM) donors. Cocultures of FT with SBM and ABM, depleted of Thy1+ or of CD3+ cells, resulted in equal proportions of lymphocytes from both BM donors. When peripheral blood lymphocytes (PBL) from synegenic or semi-allogeneic donors (F1[C57BL/KaxC57BL/6J], Thy1.1/Thy1.2); or F1[C57BL/KaxBALB/c], Thy1.1/Thy1.2, respectively) were added to these cultures, the total lymphocyte count per thymic lobe decreased and a developmental preference of the SBM-derived cells, as compared to the ABM-derived cells, was noted. Cells of the PBL types were also observed in the cultures. Cocultures of FT with ABM and PBL showed reduced proportions of ABM-derived cells and occurrence of cells of the PBL type. Finally, FT explants partially depleted of lymphocytes by irradiation (6 Gy), were cocultured with PBL from either syngeneic or allogeneic donors. In the presence of syngeneic PBL, the total number of cells and the proportion of double-positive (CD4+CD8+) T cells were similar to those in the FT cultured by itself, whereas in the presence of allogeneic PBL these values were reduced. The study suggests that mature T lymphocytes may play a role in the developmental processes in the thymus, and points to MHC-linked selective effects.

Lymphocyte development in irradiated thymuses was analyzed using two complementary strategies: an in vitro experimental model and computer simulations. In the in vitro model, fetal thymus lobes were irradiated and the regeneration of cells that survived irradiation were examined, with the results compared to those of reconstitution of the thymus by donor bone marrow cells and their competition with the thymic resident cells. In vitro measurements of resident cell kinetics showed that cell proliferation is slowed down significantly after a relatively low (10 Gy) irradiation dose. Although the number of thymocytes that survived irradiation remained low for several days post-irradiation, further colonization by donor cells was not possible, unless performed within 6 h after irradiation. These experimental results, coupled with the analysis by computer simulations, suggest that bone marrow cell engraftment in the irradiated thymus may be limited by the presence of radiation-surviving thymic resident cells and the reduced availability of seeding niches.

The study was designed to determine whether the developmental potential of immature thymocytes in the thymus is altered in aging, and whether concomitantly present mature T cells have any feedback effect. The strategy was to seed sorted double negative, CD4−CD8−(DN) thymocytes on their own, or in the presence of mature T cells, onto lymphoid depleted fetal thymus (FT) explants, and to examine the resulting T cell subsets. Thymocyte donors were young (2–3 months) and old (24 months) C57BL/6J, Thy1.2 mice and splenocytes were from C57BL/Ka, Thy1.1 mice. The DN cells of the old gave rise to lower values of double positive CD4+CD8+ (DP) cells than those of the young. Cocultures containing a mixture of DN thymocytes and CD4+CD8− splenocytes showed higher CD4+CD8− and DN, and lower DP and CD4−CD8+ levels in the old-donor derived cells, as compared with the young ones. Similar results were obtained with CD4+CD8− thymocytes. In contrast, the presence of CD4−CD8+ splenocytes had no effect on the pattern of DN cell development. Our data indicate that differentiation of CD4/CD8 thymocyte phenotypes is affected by CD4+ cells, in an age-associated differential manner.

The process of T cell generation in the thymus involves complex cell-cell interactions between the various types of thymic stromal cells, thymocyte progenitors, thymocytes at different stages of differentiation and external factors. We applied the tool of mathematical modelling to analyze hypotheses and direct experiments concerning mechanisms underlying the observed developmental inferiority of bone-marrow thymocyte progenitors from old mice. Previous experimental data showed that lower cell numbers were obtained from old bone marrow-derived thymocyte progenitors, compared to young bone marrow-derived progenitors, when colonizing simultaneously the same fetal thymus. In this study, simulations based on the mathematical model indicate that the developmental inferiority of old bone marrow-derived progenitors cannot be explained by a change in a single parameter, such as the observed differences in progenitor frequency, an increase in cell cycle duration, a reduction in the fraction of proliferating cells in old age, and/or an increase in the rate of cell death. We have performed experimental measurements of the fractions of cycling cells. No significant difference was found between these fractions in young and old bone marrow-derived thymocytes. The difference in developmental patterns of young and old bone marrow-derived thymocytes may be due to a combination of more than one mechanism, possibly including interactions between competing thymocytes of old and young bone marrow origin.

The role of major histocompatibility complex (MHC) class I and II molecules in the process of colonization of the thymic microenvironment by lymphohemopoietic cells was analyzed in an in vitro experimental model. When lymphoid-depleted fetal thymus (FT) explants were cocultured with a mixture of bone marrow (BM) cells, from donors syngeneic and allogeneic to the FT, the cells syngeneic to the FT showed a developmental preference. Treatment of these cocultures with antibodies to MHC class I (H-2D, H-2K) or class II (I-E, I-A) molecules of the syngeneic cells led to preferential development of the allogeneic donor type cells. Incubation of either the FT or the BM cell inoculum with the antibodies prior to coculture indicated that the effect was exerted on the BM cells rather than on the thymic stroma.

The effect of the thymic microenvironment on thymocyte development from lymphohemopoietic cells was studied in an in vitro experimental model. Fetal thymus explants (FT, 15 days of gestation, C57BL/Ka, Thy1.1) were cocultured with bone marrow (BM) cells of severe combined immunodeficient (SCID, C.B-17 scid/scid) or of normal BALB/c mice. The FT explants were depleted of their own lymphocytes either by irradiation (10 or 20 Gy) or by 2-deoxyguanosine (dGua) treatment. Development of SCID BM-derived Thyl+ cells was observed in coculture with the severely lymphocyte-depleted FT explants (dGua, 20 Gy), whereas BALB/c BM-type T cells were also apparent in the mildly irradiated (10 Gy) FT. The SCID BM-derived thymocytes were characterized as CD3- subpopulations expressing CD4/CD8 markers, while CD3+ CD4/CD8 subsets developed from the BALB/c mice. In contrast to results on BM-derived cells, cocultures of FT with thymus cells from SCID mice yielded CD3- CD4- CD8- Thy1.2+ cells, as opposed to BALB/c-derived Thy1.2+CD3+ cells exhibiting different CD4/CD8 phenotypes. Our data indicate that the BM cells from SCID mice can be induced to limited differentiation within the thymic microenvironment and this seems to be inhibited in the presence of resident radioresistant thymic cells.

Patterns of lymphocyte development in the thymus were analysed, focusing on newly emigrating bone marrow (BM) and resident thymic cells. We co-cultured foetal (Day 15 of gestation) thymic explants (FT, C57BL/Ka, Thy-1.1), with BM cells from young (2-3 months) or old (24 months) syngeneic, Thy-1 congenic (C57BL/6J, Thy-1.2) mice. When the FT was severely depleted [treated with either 2-deoxyguanosine (dGua) or exposed to an irradiation dose of 20 Gy] BM-type T lymphocytes were dominant, regardless of BM donor age. When the FT was only partially depleted of its proper lymphoid cells (by exposure to 10 Gy), the lymphocytes which developed were from both BM and FT origins, yet the level of donor-type thymocytes from the young mice was higher than that of the old. Under these conditions the proportion of FT-derived double-positive CD4+ CD8+ (DP) cells was higher, and that of single-positive CD4- CD8+ cells was lower, than in the BM-derived cells, irrespective of the BM donor age. The proportions of old BM-derived DP cells were lower than in the young. Co-cultures of thymus cells from young and old mice with partially depleted FT explants resulted in similar proportions of CD4/CD8 subsets from both donor and FT origins, with the exception that in the presence of old-thymus cells there was an increase in the level of FT-type CD4- CD8+ cells. Patterns of T-cell differentiation in the thymus thus seem to be determined by newly emigrating cells and the resident thymocytes.

A decline in the capacity of bone marrow cells to differentiate to T lymphocytes was found when cells from young and old donors were seeded onto an alymphoid fetal thymus. A step-by-step analysis of cell-cell interactions of the lymphohemopoietic cells and the thymic stroma indicated an effect of age on a variety of cell differentiation parameters. These included a decrease in the affinity of bone marrow cells to the stroma, and in their capacity to compete with the thymic lymphoid resident cells on colonization of the thymus. There was a significant decrease in the ability of cells of old donors to replicate sequentially within the thymic microenvironment. There was a reduced capacity of bone marrow cells from aging mice to express a developmental preference after seeding onto a syngeneic fetal thymus in a mixture with cells from allogeneic donors. We addressed the question whether the aging thymus contains increased levels of immature cells that fail to differentiate in the involuted thymic microenvironment by seeding thymocytes from young and old donors onto the fetal thymic stroma. The values of T cells that developed from the old donor inoculum were lower under these conditions. Our studies suggest that at least some of the manifestations of aging in the T cell compartment are related to developmentally programmed events in the lymphohemopoietic cell compartment.

This study examined the involvement of c-fos protooncogene in thymocyte development from lymphohemopoietic T cell progenitors, within the thymic microenvironment. We first analyzed the thymocytes developing in vitro in the fetal thymus from the c-fos transgenic mice and found a high proportion of CD4+ single positive (SP) cells. We then seeded either fetal liver or bone marrow (BM) cells from normal donors onto lymphocyte-depleted fetal thymus explants of c-fos transgenic mice. The results showed an increased proportion of mature CD4+ SP and decreased CD4+CD8+ double positive (DP) cells. A similar pattern of CD4/CD8 thymocyte subsets was observed when either thymus or BM cells from c-fos transgenic mice developed within a normal thymic stroma. The kinetics of thymocyte development in organ culture (from Days 3 to 11) suggested that the SP cells obtained under these conditions may have bypassed the CD4+CD8+ DP phase. It appears that the altered pattern of thymocyte development manifested in adult c-fos transgenic mice can be induced by the early embryonic thymic stroma, and may also involve cells in the lymphohemopoietic tissues.

Annals of the New York Academy of SciencesVolume 673, Issue 1 p. 240-251 Aging in the T Lymphocyte Compartment A Developmental Viewa A. GLOBERSON, Corresponding Author A. GLOBERSON Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelCorresponding author.Search for more papers by this authorA. SHARP, A. SHARP Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorM. FRIDKIS-HARELI, M. FRIDKIS-HARELI Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorT. KUKULANSKY, T. KUKULANSKY Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorL. ABEL, L. ABEL Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorA. KNYSZYNSKI, A. KNYSZYNSKI Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorR. EREN, R. EREN Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this author A. GLOBERSON, Corresponding Author A. GLOBERSON Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelCorresponding author.Search for more papers by this authorA. SHARP, A. SHARP Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorM. FRIDKIS-HARELI, M. FRIDKIS-HARELI Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorT. KUKULANSKY, T. KUKULANSKY Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorL. ABEL, L. ABEL Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorA. KNYSZYNSKI, A. KNYSZYNSKI Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this authorR. EREN, R. EREN Department of Cell Biology The Weizmann Institute of Science Rehovot 76100, IsraelSearch for more papers by this author First published: December 1992 https://doi.org/10.1111/j.1749-6632.1992.tb27459.xCitations: 13 a This work was supported by the Sandoz Foundation for Gerontological Research, by the Austrian National Bank, Jubiläumsfondsprojekt Nr. 3556, by a grant from the United States-Israel Binational Science Foundation, Jerusalem, and by a grant from the Chief Scientist, Israel Ministry of Health. A. G. is the incubment of the Harriet and Harold Brady Chair in Cancer Research. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1 Shortman, K., A. Wilson, M. Egerton, M. Pearse & R. Scollay. 1988. Cell. Immunol. 113: 262–479. 10.1016/0008-8749(88)90042-1 Web of Science®Google Scholar 2 Raulet, D. H., R. D. Garman, H. Saito & S. Tonegawa. 1985. Nature 314: 103–167. 10.1038/314103a0 CASPubMedWeb of Science®Google Scholar 3 Haars, R., M. Kronenberg, W. M. Gallatin, I. L. Weissman, F. L. Owen & L. Hood. 1986. J. Exp. 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