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PubMed1979

Expression of Ly-6 alloantigen during differentiation of cytotoxic T cells.

We have prepared anti-Ly-6.2 by immunization of (CBA/Ca X A-Thy-1a)F1 with AKR/Crc lymphocytes and used the antiserum to study heterogencity of peripheral T lymphocytes. The Ly-6 alloantigen is found on all activated cytotoxic T cells studied, directed to a variety of different target antigens. The antiserum reveals heterogeneity among the precursors of T killer cells, i.e. allogeneic precursors are Ly-6-, whereas the generation of cytotoxic cells to hapten-modified syngeneic cells and xenogeneic cells is partially abrogated by serum pretreatment. Precursors of some in vivo primed responses are also Ly-6+. These findings indicate that the expression of Ly-6 antigen is, at least, partially related to the stage of T cell activation. The in vitro proliferative response of T cells to allogeneic Ia antigens is substantially reduced by pretreatment with anti-Ly-6.2 serum suggesting that this antiserum may be a useful tool for the study of heterogeneity in the Ly-1+ pool of T cells.

Animals↗
PubMed1980

Organ specificity of lymphocyte migration: mediation by highly selective lymphocyte interaction with organ-specific determinants on high endothelial venules.

Evidence is presented that the organ specificity of lymphocyte migration is determined by selective interaction of lymphocytes with specialized endothelial cells. Mouse Peyer's patch and lymph node lymphocytes bind preferentially to high endothelial venules (HEV) in frozen sections of Peyer's patches and peripheral nodes, respectively, and this in vitro binding preference accurately predicts their differential segregation in vivo 30 min after i.v. injection. Both in vivo and in vitro, about 1.4 times as many as many Peyer's patch as lymph node lymphocytes bind HEV in Peyer's patches, and, conversely, twice as many lymph node cells interact with HEV in nonmesenteric lymph nodes. Even greater specificity is shown by certain homogeneous lymphocyte populations, i.e. thymic lymphomas. Some lymphomas bind with remarkable selectivity to HEV in Peyer's patches, and others interact almost exclusively with those in lymph nodes indicating that the mechanisms mediating selective recognition of HEV are capable of nearly absolute discrimination. Mesenteric node HEV are unique in that they allow both Peyer's patch- and lymph node-specific cells to bind. It is proposed that lymphocyte surface receptors specific for organ-restricted endothelial cell determinants mediate the antigen-independent organ specificity of lymphocyte migration. According to this model, there are at least 2 sets of complementary lymphocyte and endothelial cell receptors, one mediating lymphocyte-HEV adherence in Peyer's patches, the other in lymph nodes.

Animals↗
PubMed1980

A monoclonal antibody blocking human T cell function.

The possible functional role of T cell surface antigens defined by monoclonal antibodies was investigated. Five monoclonal anti-T cell reagents as well as an anti-Ia and anti-beta 2-microglobulin antibody were examined for their effect on T cell function. It was shown that an antibody termed anti-T3, reactive with all peripheral T cells, blocked T cell proliferative responses to soluble and cell surface antigens. This inhibition was seen when T lymphocytes were treated with as few as 10(4) anti-T3 molecules per cell. Although anti-T3 could block the generation of cytotoxic T cells in mixed lymphocyte culture, once generated, anti-T3 had no effect on cytotoxicity. In addition, anti-T3 abrogated the ability of T cells to provide help to B cells in a pokeweed mitogen-driven immunoglobulin system. More importantly, these functional effects were not seen with the other monoclonal antibodies. Both the appearance of this antigen in intrathymic ontogeny and its critical role in T cell function suggests that the T3 molecule is related to an important antigen recognition receptor or cell-cell interactions molecule.

Antibodies↗
PubMed1982

Recruitment of functional subpopulations of T lymphocytes. Initiator T lymphocytes recruit helper T cells for cytotoxic response.

Initiator T (Ti) lymphocytes are defined by their ability to recruit other T cell populations in vivo. In this study the function of T cells recruited into draining lymph nodes following injection of Ti cells primed to alloantigens in mixed lymphocyte culture was examined. The results demonstrate that alloantigen-specific helper T cells that interact with cytotoxic T (Tc) lymphocyte precursors are recruited, as shown by the significantly higher frequencies of helper cells in draining lymph nodes compared with controls. However, neither Tc cells nor their precursors are recruited. Recruitment by Ti lymphocytes is therefore selective for certain T cell subsets. Proposals to explain the mechanism, specificity, and selectivity of recruitment are discussed. We suggest that Ti cells have a central role in both the initiation of T cell-dependent immune responses and in the maintenance of immunologic memory. Their function is the rapid mobilization of T cell subclasses to a regional lymphoid organ where the immune response subsequently develops.

Animals↗
PubMed1982

T-T cell interactions during cytotoxic T cell responses. IV. Murine lymphoid dendritic cells are powerful stimulators for helper T lymphocytes.

Enriched populations of Ia+ Fc receptor-negative dendritic cells were compared to other cell types for their stimulatory activity in primary mixed lymphocyte reactions to alloantigens and 2,4,6,-trinitrophenylated syngeneic cells. Dendritic cells were 20-100 times more effective than unfractionated splenocytes. A second cell type exhibiting strong stimulatory activity was an Ia+ Fc receptor-positive transiently adherent cell. Both types of stimulatory cells were only effective when able to produce the monokine interleukin 1. Thus glutaraldehyde-fixed cells were not stimulatory unless extraneous interleukin 1 was added. Stimulation of helper cells by either dendritic cells or Ia+ Fc receptor-positive cells resulted in the production of interleukin 2. The data are discussed in view of the recently formulated interleukin model as a minimal scheme to explain T-T cell interactions during the in vitro induction of cytotoxic T lymphocytes.

Animals↗
PubMed1982

Role of veiled cells in lymphocyte activation.

Peripheral blood lymphocytes from normal rabbits or from rabbits hyperimmunized with human immunoglobulin were cultured in 20-microliters hanging droplets. The cultures were stimulated with concanavalin A or, in the case of cells from sensitized animals, with human immunoglobulin. The addition to the cultures of small numbers of autologous or allogeneic veiled cells separated from afferent lymph increased the responses to low doses of the stimulants, particularly when the cells were cultured at low cell densities or for short periods of time. At high cell densities or at longer periods of culture, stimulation occurred in the absence of added veiled cells and was associated with clumping of the lymphoid cells and development of cells which morphologically resembled veiled cells found in afferent lymph. The enhanced responses upon addition of small numbers of veiled cells were also correlated with the formation of lymphoid aggregates which were frequently held together by the elongated processes of a single veiled cell. The observations support the view that the veiled cells are lymph-borne precursors of dendritic cells in the lymph nodes. This may provide an in vitro model for the cellular relationships which occur in paracortical cords of lymph nodes following antigenic stimulation.

Animals↗
PubMed1984

Influenza A hemagglutinin-specific T cell clones strictly restricted by HLA-DR1 or HLA-DR7 molecules.

The antigenic specificities, major histocompatibility complex restrictions and functional properties of influenza virus-specific proliferative cloned cell lines have been studied. These lines were specific for the H3 hemagglutinin subtype of influenza A viruses. By using a large panel of HLA-phenotyped antigen-presenting cells, it was found that the polymorphic structures, defined as DR1 and DR7 molecules, or closely associated structures, function as the restricting elements. We excluded for these lines a possible restricting role of supertypic specificities, known cross-reacting elements on DR molecules, or products of other loci in known linkage disequilibrium with the HLA-DR molecules. Such exquisitely restricted clones might be of great help in the class II typing of antigen-presenting cells. Their specific activity was stable for several months. This has allowed the study of some functional properties of these long-term-cultured cloned cell lines: interleukin 2 sensitivity and production, helper function in specific antibody synthesis and ability to stimulate in mixed leukocyte reactions.

Adult↗
PubMed1984

T-T cell interactions during in vitro cytotoxic T cell responses. VI. The role of T cell-derived colony-stimulating factor in helper T cell activation.

A limiting dilution culture system has been used to analyze the role of T cell-derived colony stimulating factor (CSF) during the activation of IL 2-producing helper T lymphocytes (HTL). EL4 thymoma-derived supernatant (EL4-SN) increased about 4-fold the frequency of HTL precursors responding to metabolically active allogeneic stimulator cells. Upon biochemical separation this biological activity within the EL4-SN segregated from interleukin 2 (IL 2) and gamma interferon but was associated with or identical to CSF. Further, a comparable rise in HTL precursor frequencies was observed when semipurified interleukin 1 (IL 1) derived from the P388 D1 cell line was added to limiting dilution cultures. In contrast to IL 1, semipurified CSF failed to facilitate the activation of HTL precursors when heat-treated allogeneic spleen cells were used as stimulator cells. Because EL4-derived CSF was found to induce IL 1 production by macrophages we conclude that T cell-derived CSF amplifies, via stimulation of antigen-presenting cells the number of inducible HTL precursors. Therefore, the CSF/IL 1-dependent increase in HTL precursor frequencies reported here may reflect the differential activation threshold of HTL-precursors, most of which will not be activated by antigen per se but only in presence of additional cytokines.

Animals↗
PubMed1985

Recombinant interleukin 2 differentiates alloantigen-primed Lyt-2+ T cells into the activated cytotoxic state.

The possibility of the generation of secondary cytotoxic T lymphocyte (2 degrees CTL) activity from alloantigen primed T cells by genetically homogeneous recombinant human interleukin 2(G-IL2) was analyzed. Not only purified IL2 by cell culture (C-IL2) but also G-IL2 induced 2 degrees CTL activity from primed T cells generated in mixed lymphocyte culture. This induction process required RNA and protein synthesis, while DNA synthesis was not relevant. In parallel to the induction of 2 degrees CTL activity, transition of the primed cells from the resting G1a to activated G1b has taken place. 2 degrees CTL activity was induced from nylon column-purified primed T cells in the absence of accessory cells and also in the absence of Lyt-1+ T cells. Interferon-gamma (IFN-gamma) induction was detected during the course of activation of alloantigen-primed T cells into the cytotoxic state. When IL2 was absorbed, IFN-gamma in the culture supernatant did not induce 2 degrees CTL activity. These results suggest that the IL2 molecule possessing T cell growth factor properties shares the nature of differentiation factor in terms of the activation of alloantigen-primed T cells into cytoxic state. The role of IFN-gamma produced in situ for this activation process awaits further investigation.

Animals↗
PubMed1986

Contact interaction between lymphocytes is a general event following activation and is mediated by LFA-1.

When lymphocytes are activated in vitro, discrete cell-cell contacts are initiated which result in cluster formation. This contact interaction is found in syngeneic or allogeneic mixed leukocyte reactions as well as in mitogen-stimulated cultures (concanavalin A, periodate, lipopolysaccharide). T cells as well as B cells display the binding phenomenon. This activation-dependent lymphocyte-lymphocyte adhesion involves LFA-1, since monoclonal antibodies (including Fab fragments) against this molecule inhibit adhesion between clustering lymphocytes in a dose-dependent manner, whereas antibodies directed to several other cell surface antigens are inactive. Since a wide variety of functional interactions are inhibited by antibodies to LFA-1, it may be concluded that LFA-1-mediated cell contact is a discrete and essential step between a recognition event and the generation of functional activities by lymphocytes in general.

Aged↗
PubMed1987

Human large granular lymphocytes induce immunoglobulin synthesis after bone marrow transplantation.

Following T cell-depleted bone marrow transplantation, helper T cell numbers remain depressed for some months. Nonetheless, functional B cells can be adoptively transferred to the recipients of such grafts, where they continue to secrete antibody. We now show that immunoglobulin production by these transferred B cells is induced by activated large granular lymphocytes (LGL) which circulate in the recipients in substantial numbers during the immediate post-transplant period. The LGL are CD3 negative and therefore provide help in an antigen-unlinked manner. Helper effects for autologous (donor) B cells are augmented by the addition of anti-LFA-2 (anti-CD2) which appears to act by blocking recruitment of LGL inhibitory to developing B cells. In contrast antibody to the beta chain of LFA-1, which effectively reduces natural killer activity of LGL, does not influence their helper function. The peripheral blood LGL fraction thus contains both helper and cytotoxic activity, which can be distinguished by appropriate monoclonal antibodies.

Antibody Formation↗
PubMed1987

Induction of suppression following autologous mixed lymphocyte reaction; role of a novel 2H4 antigen.

In this study, we have investigated the cellular and molecular basis for immunoregulatory function of T4+ cells after autologous mixed lymphocyte reaction (AMLR) activation. We demonstrated that the T4+ 2H4+ subset but not the T4+2H4- subset can proliferate maximally in response to autologous non-T cells. T4+ cells activated by AMLR exerted suppressor activity on pokeweed mitogen-driven IgG synthesis of autologous peripheral blood lymphocytes. The suppressor activity by AMLR-activated T4+ cells required the presence of fresh T8+ cells in the secondary culture, indicating that AMLR-activated T4+ cells functioned as a suppressor inducer rather than as a suppressor effector population. Following activation of T4+ cells in AMLR, it is the T4+2H4+ subset which induces suppression through the T8 population. Moreover, the treatment of AMLR-activated T4+2H4+ cells with anti-2H4 antibody, but not other antibodies, resulted in the abolishment of suppressor inducer function of such cells, suggesting that the 2H4 molecule itself may be involved in the suppressor inducer function. The 2H4 antigen on such cells was shown to be comprised of 220-kDa and 200-kDa glycoproteins. These results support the notion that the AMLR may play an important role in generating suppressor inducer signals and in down-regulating the immune response following self major histocompatibility complex recognition. More importantly, the present studies indicate that the 2H4 antigen on T4 cells serves not only as a phenotypic marker of suppressor inducer cells, but may have a functionally important role itself inducing suppression.

Antibodies, Monoclonal↗
PubMed1987

Phenotypic identification of suppressor-effector, suppressor-amplifier and suppressor-inducer T cells of B cell differentiation in man.

Using monoclonal anti-Leu8 antibody to isolate subpopulations of human helper/inducer (CD4+) and suppressor/cytotoxic (CD8+) T cells, we have investigated the role of these subpopulations in the regulation of B cell differentiation in the human autologous mixed leukocyte reaction (AMLR). Whereas AMLR-activated CD8+,Leu8- cells were capable of suppressing fresh AMLR cultures in the absence of fresh CD8+ cells, CD8+,Leu8+ cells suppressed only those cultures containing fresh CD8+ cells. On the other hand, CD8+,Leu8- cells became suppressor cells only when cultured in the presence of CD8+,Leu8+ cells. Finally, the development of CD8+ suppressor cells was dependent on the presence of CD4+,Leu8+ cells; CD4+,Leu8- cells were incapable of acting as suppressor-inducer cells, but have been shown previously to mediate T cell help for B cell differentiation. Thus, at least 3 phenotypically distinct subsets of T cells interact sequentially to generate suppression of B cell differentiation induced in the AMLR: CD4+,Leu8+ suppressor/inducer cells, CD8+,Leu8+ suppressor-amplifier cells and CD8+,Leu8- suppressor-effector cells.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

The role of lymphocyte function-associated antigen 1 (LFA-1) in the adherence of T lymphocytes to B lymphocytes.

The functional role of the LFA-1 molecule in the interaction between helper T lymphocytes and B lymphocytes was investigated using lymphocytes from patients with leukocyte adhesion deficiency, an inherited immunodeficiency characterized by a defective leukocyte expression of the LFA-1, Mac-1 (CR3) and p150,95 molecules. The ability of LFA-1- T lymphocytes to provide antigen-specific help for HLA-identical LFA-1+ B lymphocytes was reduced while their antigen-specific activation was normal. Antigen-independent conjugate formation between resting, nonactivated LFA-1- T lymphocytes and LFA-1+ B lymphocytes was impaired while LFA-1- B lymphocytes bound LFA-1+ T lymphocytes normally. Conjugate formation of activated LFA-1- T lymphocytes was mostly mediated by the CD2-LFA-3 adhesion pathway while the ICAM-1 molecule, a ligand of LFA-1, had no function. These results demonstrate that LFA-1 plays a major role in the cognate interaction between helper T lymphocytes and B lymphocytes that cannot be mediated instead by CD2 or other molecules on resting T lymphocytes.

Antibodies, Viral↗
PubMed1988

Functional interaction between B cell subpopulations defined by CD23 expression.

Using the CD23 monoclonal antibody (mAb) MHM6 and sheep anti-mouse Ig bound to magnetic beads we have obtained highly purified populations of MHM6+ and MHM6- tonsil B cells. We have found that the increased expression of MHM6 reactivity seen on B cells after activation results from up-regulation of antigen on cells already weakly positive and not from expression of new antigen on the previously negative population. The strong proliferative responses of MHM6+ cells seen in the presence of anti-IgM (alpha mu) and interleukin 4 (IL4) or the CDw40 mAb G28-5, and with Staphylococcus aureus Cowan I (SAC), and to a lesser extent with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), resemble that seen among unfractionated B cells. In contrast, the MHM6- population cultured alone responds only weakly to alpha mu + G28-5 or SAC and exhibits virtually no response to alpha mu + IL4 or TPA. With all these mitogenic stimuli, tritiated thymidine uptake by the MHM6- population is augmented three- to sixfold by the addition of mitomycin C (MC)-treated MHM6+ cells. Pretreatment of cells with anti-leukocyte functional antigen 1 mAb has little effect on the subsequent proliferation of the MHM6- population but shows cell contact to be critical for the proliferation of MHM6+ cells. Such pretreatment has revealed that the functional interaction observed between MHM6+ and MHM6- cells is dependent on both cell contact and the presence of an MHM6+ cell-derived soluble component. We have found that addition of soluble CD23, purified from Epstein-Barr virus-transformed lymphoblastoid cell line supernatant, increases the proliferative response of MHM6- tonsil B cells to mitogenic stimuli in the presence of inactivated MHM6+ cells but has no effect on proliferation when MHM6+ cells are absent. By way of contrast to normal B lymphocytes, we have examined functional responses of prolymphocytic leukemia (PLL) B cells. Although these cells, when freshly isolated, show comparable levels of CD23 expression to normal B cells, this expression is not increased upon activation. In addition, in contrast to normal B cells, the PLL MHM6- population cultured alone shows a strong proliferative response to various mitogenic stimuli, comparable to that of MHM6+ or unfractionated cells, and this response is not augmented by the addition of MC-treated MHM6+ cells. Thus, a novel functional interaction is described between normal, but not leukemic, B cell populations defined by their expression of CD23.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1988

The tumor progression-associated human melanoma antigen P3.58 mediates monocyte-lymphocyte interactions in vitro.

The melanoma-associated antigen P3.58 is rarely found on benign proliferating melanocytes but is consistently expressed on advanced malignant melanomas which have a high probability of metastasis. Previous studies have shown that its expression on normal tissues is limited to vascular endothelia and lymphoid follicle germinal centers and that it is also expressed by activated monocytes in vitro. In the studies reported here, anti-P3.58 monoclonal antibodies (mAb) were shown to partially inhibit antigen-specific and anti-CD3-induced T cell proliferation and to completely block a lymphocyte/monocyte clustering which occurs in the absence of added antigen. This inhibition is highly specific for P3.58 mAb and was not affected by mAb directed to major histocompatibility complex or T cell antigens. P3.58 therefore seems to be involved in an antigen-independent attraction or adhesion of lymphocytes. P3.58 is the second example (HLA-DR being the first) of an association between the expression of an immune function-associated molecule and the development of metastatic disease in melanoma.

Antibodies, Monoclonal↗
PubMed1991

Cytotoxic T lymphocyte precursor cells specific for the major histocompatibility complex class I-like antigen, Qa-2, require CD4+ T cells to become primed in vivo and to differentiate into effector cells in vitro.

Experiments were performed to determine whether CD4+ T cells are required for the generation of cytotoxic T lymphocytes (CTL) specific for the nonpolymorphic major histocompatibility complex (MHC) class I-like antigen, Qa-2. Splenic T cells from BALB/cBy (Qa-2b) mice that had been immunized with irradiated BALB/cJ (Qa-2a) splenocytes generated CTL following in vitro stimulation with BALB/cJ splenocytes. These CTL lysed all Qa-2+, but not Qa-2- targets, regardless of the H-2 haplotypes of target cells or their non-MHC backgrounds. This apparent MHC class I-unrestricted recognition of Qa-2 antigen was confirmed using Qa-2-specific CTL clones. The Qa-2-primed CTL precursor cells (CTLp) and CTL were found to be CD8+ T cells. Primed splenocytes depleted of CD4+ T cells prior to culture failed to generate CTL, but addition of lymphokines to the culture restored the CTL generation. Stimulation of primed splenic T cells with irradiated Qa-2+ T blast cells, instead of splenocytes or B blast cells, led to little to no CTL generation, suggesting that MHC class II molecules are involved in the presentation of Qa-2 antigen to CD4+ T cells. This was also supported by the results of experiments using Qa-2+, class II- thymoma cells of BALB/c origin. Stimulation of the thymoma-primed splenic T cells with the mitomycin C-treated thymoma cells resulted in no generation of anti-Qa-2 CTL, despite the fact that high levels of CTL specific for minor histocompatibility (H) antigens and H-2d were generated by immunizing the corresponding allogeneic hosts with the thymoma. However, the addition of lymphokines rendered thymoma-primed T cells capable of generating anti-Qa-2 CTL. Both CD4+ and CD8+ T cell populations, isolated from the BALB/cJ splenocyte-primed responder cells, proliferated in vitro in response to the Qa-2+ splenocytes, suggesting that Qa-2-reactive CD4+ T cells were present in the immunized mice. Depletion of CD4+ T cells from thymectomized BALB/cBy mice with anti-L3T4 monoclonal antibodies markedly reduced, but did not eliminate anti-Qa-2 CTL generation. In contrast, depletion of CD8+ T cells led to a complete abrogation of the CTL response. Addition of lymphokines to the culture of responder cells depleted of either T cell subset did not restore their reactivity. It is concluded that anti-Qa-2 CTLp need "help" from CD4+ T cells to become primed in vivo. Furthermore, primed CTLp also need "help" or lymphokines provided by CD4+ T cells to differentiate into effector CTL in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗