ONTOGENY OF IMMUNITY IN MAN

1975 ◽  
Vol 80 (2_Suppl) ◽  
pp. S306-S317 ◽  
Author(s):  
Daniel P. Stites ◽  
Joseph Caldwell ◽  
Martin C. Carr ◽  
H. Hugh Fudenberg
Keyword(s):  
T Cells ◽  
Human Subjects ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Lymphoid Tissues ◽  
Foetal Development ◽  
Lymphoid Development ◽  
Foetal Liver ◽  
Low Levels

ABSTRACT We have reviewed selected aspects of recent findings in the ontogeny of immunity in man. For obvious reasons, constraints placed on experimental work with human subjects, albeit deceased foetuses, limit the work to in vitro studies. Nevertheless, a number of novel and important concepts have emerged. First, as in lower animals, lymphoid development of the foetal thymus in general precedes the development of immunocompetence in peripheral lymphoid tissues. A striking exception to this rule is the finding of cells in early foetal liver which respond to allogeneic cells in the mixed lymphocyte culture some weeks before lymphoid organization of the thymus. In addition, the response of foetal cells to allogeneic cells in the mixed lymphocyte reaction (MLR) precedes the response to phytohaemagglutinin (PHA), a stimulant with relative T cell specificity. The use of markers for T cells to map the emergence of this class of lymphocytes correlates well with various functional attributes of T cells in in vitro culture systems. B cells emerge first in foetal liver at about 9 weeks' gestation, but formation of immunoglobulin by the foetus occurs at very low levels until after birth. There is a suggestion that progression from IgM to IgA synthesis occurs during human foetal lymphoid development. Taken as a whole, these data suggest a rather remarkable and perhaps unexpected degree of cellular and potential humoral immunocompetence at early stages of foetal development in man.

scholarly journals Sequential responses of mouse spleen T cells in mixed lymphocyte culture-induced cytolysis.

1975 ◽  
Vol 141 (2) ◽  
pp. 508-512 ◽  
Author(s):  
P Häyry ◽  
L C Andersson
Keyword(s):  
T Cells ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Mouse Spleen ◽  
Blast Transformation

T cells triggered to blast transformation and proliferation by histoincompatible cells have the capacity of reverting "back" to lymphocytes. These "secondary" lymphocytes and their progeny cells are able to respond repeatedly to the same allogeneic stimulus in vitro.

scholarly journals Haplotype-specific suppression of cytotoxic T cell induction by antigen inappropriately presented on T cells.

1983 ◽  
Vol 157 (1) ◽  
pp. 141-154 ◽  
Author(s):  
P J Fink ◽  
I L Weissman ◽  
M J Bevan
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Cytotoxic T Cell ◽  
Spleen Cells ◽  
Specific Suppression ◽  
Veto Cells

To detect a strong cytotoxic T lymphocyte (CTL) response to minor histocompatibility (H) antigens in a 5-d mixed lymphocyte culture, it is necessary to use a responder that has been primed in vivo with antigen-bearing cells. It has previously been shown that minor-H-specific CTL can be primed in vivo both directly by foreign spleen cells and by presentation of foreign minor H antigens on host antigen-presenting cells. This latter route is evident in the phenomenon of cross-priming, in which H-2 heterozygous (A x B)F1 mice injected 2 wk previously with minor H-different H-2A (A') spleen cells generate both H-2A- and H-2B-restricted minor-H-specific CTL. In a study of the kinetics of direct- vs. cross-priming to minors in F1 mice, we have found that minor H-different T cells actually suppress the induction of virgin CTL capable of recognizing them. CTL activity measured from F1 mice 3-6 d after injection with viable A' spleen cells is largely H-2B restricted. The H-2A-restricted response recovers such that roughly equal A- and B-restricted activity is detected in mice as early as 8-10 d postinjection. This temporary hyporeactivity does not result from generalized immunosuppression--it is specific for those CTL that recognize the foreign minor H antigen in the context of the H-2 antigens on the injected spleen cells. The injected spleen cells that mediate this suppression are radiosensitive T cells; Lyt-2+ T cells are highly efficient at suppressing the induction of CTL in vivo. No graft vs. host reaction by the injected T cells appears to be required, as suppression of direct primed CTL can be mediated by spleen cells that are wholly tolerant of both host H-2 and minor H antigens. Suppression cannot be demonstrated by in vitro mixing experiments. Several possible mechanisms for haplotype-specific suppression are discussed, including inactivation of responding CTL by veto cells and in vivo sequestration of responding CTL by the injected spleen cells.

scholarly journals Phenotype, Localization, and Mechanism of Suppression of CD4+CD25+ Human Thymocytes

2002 ◽  
Vol 196 (3) ◽  
pp. 379-387 ◽  
Author(s):  
Francesco Annunziato ◽  
Lorenzo Cosmi ◽  
Francesco Liotta ◽  
Elena Lazzeri ◽  
Roberto Manetti ◽  
...  
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Mixed Lymphocyte Culture ◽  
Interferon Γ ◽  
Lymphocyte Culture ◽  
Target Cells ◽  
Suppressive Activity ◽  
Α Chain ◽  
Tgf Β1

Phenotypic markers, localization, functional activities, and mechanisms of action in vitro of CD4+CD25+ T cells, purified from postnatal human thymuses, were investigated. These cells showed poor or no proliferation in mixed lymphocyte culture (MLC), and suppressed in a dose-dependent fashion the proliferative response to allogeneic stimulation of CD4+CD25− thymocytes. Virtually all CD4+CD25+ thymocytes constitutively expressed cytoplasmic T lymphocyte antigen (CTLA)-4, surface tumor necrosis factor type 2 receptor (TNFR2), and CCR8. They prevalently localized to perivascular areas of fibrous septa and responded to the chemoattractant activity of CCL1/I-309, which was found to be produced by either thymic medullary macrophages or fibrous septa epithelial cells. After polyclonal activation, CD4+CD25+ thymocytes did not produce the cytokines interleukin (IL)-2, IL-4, IL-5, IL-13, interferon γ, and only a very few produced IL-10, but all they expressed on their surface CTLA-4 and the majority of them also transforming growth factor (TGF)-β1. The suppressive activity of these cells was contact dependent and associated with the lack of IL-2 receptor (IL-2R) α-chain (CD25) expression in target cells. Such a suppressive activity was partially inhibited by either anti–CTLA-4 or anti–TGF-β1, and was completely blocked by a mixture of these monoclonal antibodies, which were also able to restore in target T cells the expression of IL-2R α-chain and, therefore, their responsiveness to IL-2. These data demonstrate that CD4+CD25+ human thymocytes represent a population of regulatory cells that migrate in response to the chemokine CCL1/I-309 and exert their suppressive function via the inhibition of IL-2R α-chain in target T cells, induced by the combined activity of CTLA-4 and membrane TGF-β1.

scholarly journals Effect of activated lymphocytes on the regulation of hematopoiesis: enhancement and suppression of in vitro BFU-E growth by T cells stimulated by autologous non-T cells

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1143-1147 ◽  
Author(s):  
M Harada ◽  
S Nakao ◽  
K Kondo ◽  
K Odaka ◽  
M Ueda ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Colony Growth ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
T Cell Subsets ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Erythroid Progenitor

Abstract Autologous mixed lymphocyte culture (AMLR) is an immunologic response with memory and specificity and plays a role in immune regulation. Effects of T cells activated by AMLR were studied in the regulation of in vitro erythropoiesis. AMLR-activated T cells were cocultured with autologous non-T, nonphagocytic peripheral blood mononuclear cells for assaying erythroid progenitor cells (BFU-E). T cells activated for 3 days in AMLR showed significant enhancement of in vitro colony growth by BFU-E. In contrast, activated T cells from day 7 AMLR caused significant suppression of BFU-E growth. Both enhancing and suppressing activities of AMLR-activated T cells were mediated by an la-positive and radiosensitive population within the OKT4+ subset. These observations suggest that AMLR-activated T cells may play a role in the immune-mediated regulation of in vitro erythropoiesis. It is also suggested that heterogeneous T-cell subsets may exert regulatory functions in the regulation of in vitro hematopoiesis.

scholarly journals An evaluation of the potential to use tumor-associated antigens as targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues.

1993 ◽  
Vol 177 (6) ◽  
pp. 1681-1690 ◽  
Author(s):  
J Hu ◽  
W Kindsvogel ◽  
S Busby ◽  
M C Bailey ◽  
Y Y Shi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoid Cells ◽  
Lymphoid Tissues ◽  
Normal Cells ◽  
T Cell Therapy ◽  
Tumor Associated Antigens ◽  
Low Levels

A major obstacle to the development of T cell therapy for the treatment of human tumors has been the difficulty generating T cells specifically reactive with the tumor. Most of the characterized human tumor antigens have been classified as tumor associated, because of demonstrable expression at low levels in some normal cells, and thus have not been extensively studied as potential targets of a therapeutic immune response. However, the quantitative difference in expression of such antigens between the tumor and normal cells might permit the generation of antigen-specific T cells capable of selective antitumor and not autoimmune activity. To address this issue, transgenic (TG) mice were generated that expressed low levels of Friend murine leukemia virus (FMuLV) envelope protein in lymphoid cells under the control of an immunoglobulin promoter. This protein is expressed at high levels by a Friend virus-induced erythroleukemia of C57BL/6 (B6) origin, FBL, and has been shown to serve as an efficient tumor-specific rejection antigen in B6 mice. The env-TG mice were tolerant to envelope, as reflected by the failure to detect an envelope-specific response after in vivo priming and in vitro stimulation with preparations of FMuLV envelope. However, adoptively transferred envelope-specific T cells from immunized non-TG B6 mice mediated complete eradication of FBL tumor cells in TG mice, and did not induce detectable autoimmune damage to TG lymphoid tissues. The transferred immune cells were not permanently inactivated in the TG mice, since donor T cells responded to envelope after removal from the TG mice. The lack of autoimmune injury did not reflect inadequate expression of envelope by TG lymphocytes for recognition by T cells, since TG lymphocytes functioned effectively in vitro as stimulators for envelope-specific T cells. The results suggest that this and analogous strains of TG mice may prove useful for elucidating principles for the generation and therapeutic use of tumor-reactive T cells specific for tumor-associated antigens.

scholarly journals Effect of activated lymphocytes on the regulation of hematopoiesis: enhancement and suppression of in vitro BFU-E growth by T cells stimulated by autologous non-T cells

Blood ◽  
1986 ◽  
Vol 67 (4) ◽  
pp. 1143-1147 ◽  
Author(s):  
M Harada ◽  
S Nakao ◽  
K Kondo ◽  
K Odaka ◽  
M Ueda ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Colony Growth ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
T Cell Subsets ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Erythroid Progenitor

Autologous mixed lymphocyte culture (AMLR) is an immunologic response with memory and specificity and plays a role in immune regulation. Effects of T cells activated by AMLR were studied in the regulation of in vitro erythropoiesis. AMLR-activated T cells were cocultured with autologous non-T, nonphagocytic peripheral blood mononuclear cells for assaying erythroid progenitor cells (BFU-E). T cells activated for 3 days in AMLR showed significant enhancement of in vitro colony growth by BFU-E. In contrast, activated T cells from day 7 AMLR caused significant suppression of BFU-E growth. Both enhancing and suppressing activities of AMLR-activated T cells were mediated by an la-positive and radiosensitive population within the OKT4+ subset. These observations suggest that AMLR-activated T cells may play a role in the immune-mediated regulation of in vitro erythropoiesis. It is also suggested that heterogeneous T-cell subsets may exert regulatory functions in the regulation of in vitro hematopoiesis.

scholarly journals Continuously proliferating allospecific T cells. I. Specificity of cooperation with allogeneic B cells in the humoral antibody response to sheep erythrocytes.

1979 ◽  
Vol 149 (4) ◽  
pp. 808-814 ◽  
Author(s):  
J D Waterfield ◽  
G Dennert ◽  
S L Swain ◽  
R W Dutton
Keyword(s):  
T Cells ◽  
B Cells ◽  
Humoral Response ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Strain Specificity ◽  
Sheep Erythrocytes ◽  
Effect Factor ◽  
Helper Activity

Allospecific mouse T cells, positively selected in one-way mixed lymphocyte culture were maintained for 3 yr in tissue culture by sequential restimulation. Such proliferating T cells were tested for their ability to induce a positive allogeneic effect: activating B cells in an in vitro primary humoral response to sheep erythrocytes. It was found that such T lymphocytes could function as helper cells. Helper activity was shown to be specific in that the B cells activated had to share major histocompatibility complex (H-2) antigens with the strain used for selection of the cell line. Intra H-2 mapping showed that antigens coded in the IAk subregion played an important role in the induction of the positive allogeneic effect. Supernatant factors could substitute for the allogeneic T cells in activation of the in vitro humoral response. However, such supernates exhibited no strain specificity. Therefore, the specificity seen in the positive allogeneic effect is presumably a consequence of the alloantigenic recognition receptors intrinsic to the T cells, and not to any biologically restricting properties of the allogeneic effect factor itself.

scholarly journals Autologous mixed lymphocyte culture reactions and generation of cytotoxic T cells.

1977 ◽  
Vol 146 (6) ◽  
pp. 1809-1814 ◽  
Author(s):  
R A Vande Stouwe ◽  
H G Kunkel ◽  
J P Halper ◽  
M E Weksler
Keyword(s):  
T Cells ◽  
Cell Lines ◽  
Lymphoid Cell ◽  
Cytotoxic T Cells ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Cell Generation ◽  
Cytotoxic T Cell ◽  
Cytotoxic Cells ◽  
Lymphoid Cell Lines

Autologous mixed lymphocyte culture (MLC) reactions were studied utilizing autologous purified B cells and autologous established B lymphoid cell lines as stimulating cells. Similar results were obtained although somewhat greater stimulation of lymphocyte proliferation was found with the autologous lymphoid cell lines. Cytotoxic T cells were not generated against the stimulating cells in either case when peripheral blood cells were used as targets. A low cytotoxicity was detected when lymphoid cell lines were used both as stimulators and target cells. However this was nonspecific and was always greater for heterologous lines than for the stimulator line. Third-party cell experiments demonstrated that the autologous reaction could serve as a proliferative stimulus for specific cytotoxic lymphocyte generation. Heat-treated allogeneic lymphocytes that alone do not stimulate proliferation ro cytotoxic T-cell generation in MLC reactions when added to the autologous system produced specific cytotoxic cells. The separation of the proliferative phase from the cytotoxic cell generation was especially striking in these experiments. Possible uses of this system for the generation of specific cytotoxic cells to other nonstimulatory cells are discussed.

Sign in / Sign up

Export Citation Format

Share Document