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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]

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]

Immunological reactivity in patients with systemic lupus erythematosus (SLE) was assessed by investigating in vitro trinitrophenyl (TNP)-specific antibody formation by peripheral lymphocytes. Peripheral lymphocytes from 16 patients with SLE were cultured with TNP conjugated with horse erythrocytes (TNP- HRBC) in the presence of 2-mercaptoethanol. The hemolytic plaque assay was used to detect hapten (TNP)-specific antibody-forming cells. Peripheral lymphocytes from normal individuals failed to produce antibody to TNP, whereas SLE lymphocytes produced a significant number of plaque-forming cells. Co-culture experiments with SLE and normal lymphocytes suggested that patients with SLE have a defect in T lymphocytes, leading to abnormal antibody production. [ABSTRACT FROM AUTHOR]

The present experiments were undertaken to delineate the role of LD and SD antigens in terms of memory in cell-mediated immune response (CML), Using recombinants that differ for either the H-2K or H-2D determinants (SD-different) and other recombinants differing for the central region of H-2 (LD different), we have investigated this question. The results indicate that priming to SD determinants leads to a more rapid and higher response when cells are restimulated in vitro with either the same SD antigt-n alone or the same SD plus an LD antigen and tested on target cells that possess either the SD antigen alone or both the LD and SD antigens. Antigens in the central regions of H-2, which includes LD, serve as the stimulus both for the helper T cells and for the c)'totoxic T lymphocjtes. Priming with a high dose of LD antigt-ns leads to memory in the cytotoxic T lymphocyte recognizing the cytotoxic target antigens coded by the central region of H-2. Nevertheless, memory could not be detected when priming was done under the same conditions as for SD antigens. Moreover, a primed helper T-cell response does not facilitate the development of increased CML on restimulation in vitro with the LD antigen used for priming and a new SD antigen. Thus, it seems that memory in CML is in the cytotoxic T lymphocyte and not in the proliferating helper cells. [ABSTRACT FROM AUTHOR]

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]