Search

There is no doubt that HLA-DR molecules are acting as the products of HLA-linked immune response genes (Ir-genes), because (i) HLA-DR molecules are the restriction elements in the interaction between CD4+ helper T cells and antigen-presenting cells (APC) to respond to many antigens such as streptococcal cell wall antigen (SCW) (Nishimura & Sasazuki, 1983; Sone et al., 1985; Hizayama et al., 1986), schistosomal antigen (Sj) (Hirayama et al., 1987), Mycobacterium leprae antigen (ML) (Kikuchi et al., 1986) and so on; and (ii) anti-HLA-DR monoclonal antibodies completely abolish the immune response to those antigens (Nishimura & Sasazuki, 1983; Sone et al., 1985). However, genetic analysis of the immune response to those antigens in families or populations revealed that responsiveness is recessive and non-responsiveness to those antigens is a dominant genetic trait that is tightly linked to HLA (Sasazuki et al., 1980a, 1983; Watanabe et al., 1988). This is completely opposite to the situation under the Ir-gene control where responsiveness is dominant and non-responsiveness is recessive. In this paper, we report evidence of how we came across the concept of HLA-linked immune suppression genes (Is-genes) besides Ir-genes, and show evidence for the epistatic interaction between HLA-DR and DQ to determine the immune response to several antigens in humans. [ABSTRACT FROM AUTHOR]

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]

A theoretical framework is presented which explores two models of suppressor cell-target cell interactions in T-dependent antibody responses. The first is the full-dominance model, in which a single or limited number of suppressor cells can entirely suppress an immune response irrespective of the multiplicity of other effector cells present. The second is the ratio-dominance model, in which a suppressor cell is capable of inactivating only a certain number of target cells. Thus, the multiplicity of target cells in a given microculture well influences the degree of suppression. Both models are evaluated using limiting dilution analysis and two systems are explored, in the first model, suppressor cells alone are titrated into microculture wells containing all other cells required for an immune response. In the second, suppressor cells are added from populations containing a mixture of helper T cells as well as suppressor cells. This latter type of analysis is similar to that in which populations of T cells primed to alloantigens in mixed lymphocyte cultures are analysed for positive (help) and negative (suppression) allogeneic effects. The analysis allows us to conclude that such suppressor cells operate via a mechanism best described by a ratio-dominance model. [ABSTRACT FROM AUTHOR]

Summary: It is unclear whether γδ T cells are involved in humoral immunity against Plasmodium infection. Here, we show that B‐cell‐immunodeficient mice and γδ T‐cell‐deficient mice were incapable of protecting against Plasmodium berghei XAT parasites. γδ T‐cell‐deficient mice developed reduced levels of antigen‐specific antibodies during the late phase of infection. The numbers of follicular helper T cells and germinal centre B cells in γδ T‐cell‐deficient mice were lower than in wild‐type mice during the late phase of infection. Expression profiling of humoral immunity‐related cytokines in γδ T cells showed that interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) are increased during the early stage of infection. Furthermore, blockade of IL‐21 and IFN‐γ signalling during the early stage of infection led to reduction in follicular helper T cells and germinal centre B cells. γδ T‐cell production of IL‐21 and IFN‐γ is crucial for the development and maintenance of follicular helper T cells and germinal centre B cells during the late phase of infection. Our data suggest that γδ T cells modulate humoral immunity against Plasmodium infection. γδ T cells produce interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) during the early phase of Plasmodium infection. The γδ T‐cell‐produced IL‐21 and IFN‐γ elicit the development/maintenance of follicular helper T cells and germinal centre B cells during the late phase of Plasmodium infection. [ABSTRACT FROM AUTHOR]

The history of regulatory T cells goes back to the realisation that T cells could provide ‘help’ for antibody responses: the obverse of this is their ability to hold them in check. This brief personal overview follows the initial designation of T cells as ‘suppressor’ and the various hypotheses, some now disproved, put forward for their mechanism of action. We now cautiously label them T regulatory cells, but realise they do not control not all immune regulation. They probably operate through several mechanisms, and some of these are discussed. [ABSTRACT FROM AUTHOR]

The physical association of dendritic cells and T lymphocytes in clusters is required for primary immune responses. We have used oxidative mitogenesis as a model to examine the requirements for accessory cell-T-cell clustering and T-cell activation; in this polyclonal response, periodate-treated T cells cluster with dendritic cells (DC) and proliferate. Here we observed firstly that macrophages (Mφ) but not B cells or B blasts could also cluster with periodate-treated T cells, but they did not stimulate proliferation. Thus, clustering with a cell that can express MHC class II (Ia) molecules and synthesize interleukin-1 (IL-1) is not sufficient for mitogenesis, and Ia expression is not sufficient for clustering. Secondly, that proliferation in oxidative mitogenesis and the allogeneic mixed leucocyte reaction (MLR) was inhibited by CD18, CD4 and CD8 antibodies but not, with one exception, by others of the panel tested. Thirdly, using rapid cluster assays we showed that DC and Mφ formed temperature-dependent clusters with syngeneic and allogeneic periodate-treated T cells. Clustering was inhibited by CD18 antibodies, probably at the level of the T cell but not the accessory cell, and this may be a general feature of such inhibition. However, CD4 and/or CD8 antibodies did not affect clustering, showing that these molecules are involved in subsequent stages of T-cell activation. Since clustering of DC and Mφ with periodate-treated T cells requires CD18, but only the former leads to proliferation, we conclude that CD18-dependent clustering is not sufficient for mitogenesis. [ABSTRACT FROM AUTHOR]

Spleen cells, obtained 2-5 days after in vivo priming with sheep erythrocytes (SRBC), were cultured to determine the presence of plaque-forming cell (PFC) precursors capable of developing into mature PFC under the influence of various stimulants. Lipopolysaccharide (LPS), added together with SRBC at the initiation of a 48-hr in vitro culture, enhanced the PFC response of primed spleen cells. In vivo priming for a minimum of 3 days was required, and maximal numbers of PFC were obtained from spleen cells primed for 4 days. Depletion of T lymphocytes from Day 3-primed spleen cells abrogated LI'S-mediated enhancement, and addition of concanavalin A supernatants to the T-cell depleted system restored the enhancement, suggesting that LPS action required co-operation with a product(s) of activated T cells. Addition of various interleukin-2 preparations including recombinant human IL-2 to the system restored the LPS-mediated enhancement. The response of Day 3 cells from which T cells were eliminated as vigorously as possible was similarly restored by the addition of IL-2, LPS and antigen, suggesting that IL-2 reacts directly with PFC precursors that have developed IL-2 receptors. LPS-mediated enhancement, in the presence or absence of T cells, was also markedly dependent on the presence of SRBC during in vitro culture. These data suggest that, in co-operation with IL-2 and other co-factors, antigen plays a significant role in driving the later stages of differentiation and/or division of PFC precursors to mature PFC. [ABSTRACT FROM AUTHOR]

Mechanisms by which T and B lymphocytes co-operate in the in vitro secondary antibody response to trinitrophenyl-conjugated soluble protein antigens were investigated. The generation of antibody responses was analyzed when haptenic and carrier determinants were either linked or non-linked. Ability to co-operate through each of these mechanisms was influenced by the experimental conditions employed, particularly the mode of preparation of the T cells and the antigen concentration used. Nylon wool filtration of T cells may deplete a T helper population involved in non-linked recognition interactions.

Small lymphocyte subsets were characterized radioautographically on the basis of several surface markers, viz. surface Ig (S-Ig), Thy-1 and Lyt (Ly-1, Ly-2 and 3) antigens in host lymphoid organs (thymus, spleen and blood) as well as at the turnout site at various stages of subcutaneous growth of two different syngeneic turnouts—MPC-11 plasmacytoma and WEH I- 164 fibrosarcoma in BA L B/c mice. In both tumour-host combinations there was a rise in the levels of null (S-Ig-, Thy-1-) small lymphocytes as well as the Ly-23+ subset of T small lymphocytes at all the sites examined. The absolute number of these two subsets also increased excepting the case of null cell rise in the thymus which was relative. The functional potentials of Lyt subsets were explored by employing in vitro and in vivo assays. While no appreciable levels of anti-turnout cytotoxic T cells (Tc) were detectable by a 51Crk release assay in the host spleen or the turnout-draining lymph nodes at any stage of growth of MPC-11 tumour, such Tc was generated in vitro by a co-cultivation of unprimed spleen cells with irradiated MPC-11 cells. These Tc were Thy-l+ and Ly-12+, as noted from antibody+C' mediated abrogation of cytotoxicity. These results suggested that the generation of anti-turnout Tc in vivo was suppressed in tumour-bearing hosts. The possibility of a cell-mediated suppression was tested by an adoptive transfer of thymocytes or splenocytes from turnout-bearing mice into naive or pre-immunized recipients which then received fresh turnout transplants. This procedure caused a specific enhancement of turnout growth in three tumour-host combinations: MPC-I 1 or WEHI-164 turnout in BALB/c mice and W-I fibrosarcoma in CBA mice. The suppressor lineage lymphocytes appearing in vivo were found to be Thy-1+ and Ly-1-, 2+, as noted from antibody +C' mediated abrogation of their turnout-growth promoting ability. They appeared earlier (7 days) in the thymus and later (> 2 weeks) in the spleen and then persisted during the turnout lifetime. The parallel kinetics of the increase in the overall level of Ly-23+ cells and the appearance of Ly-2(3)+ suppressor lineage T cells in tumour-bearing hosts may indicate that studies of T-cell surface markers may be useful in predicting changes in the functional lymphocyte subsets. [ABSTRACT FROM AUTHOR]

A non-specific immunoenhancing factor from leukaemia owl monkey peripheral T lymphocytes has been purified and partially characterized. Owl monkey enhancing factor, OMEF, is a glycoprotein with a molecular weight of 39,000 and an isoelectric point of pH 6·5. It acts at nanogram levels on day 2 of the in vitro immune response to enhance the number of plaque-forming cells produced to sheep red blood cells in a routine assay system but has no effect when added on day 0 to this system. Antibodies to the purified factor have been produced and binding studies show that OMEF cross-reacts with other anti- sera raised to an enhancing factor produced by a mixture of human allogeneic lymphocytes but shows no cross-reactivity to a murine enhancing factor. [ABSTRACT FROM AUTHOR]