Richard K. Gershon

T cell control of antibody production.

The discovery that the thymus was involved in the development of the immune system (Miller, 1961; Archer et al, 1962; Jankovic et al, 1962) ushered in the “golden age of ‘thymology’” (Miller, 1967). A second golden age (Miller, 1967) began with the discovery that thymus-derived lymphocytes [soon to be christened T cells (Roitt et al, 1969)] did not themselves make circulating antibodies, but rather assisted other nonthymus-derived lymphocytes to do so (Miller and Mitchell, 1969; Davies, 1969; Claman and Chaperon, 1969). This second class of lymphocytes was christened B cells (Roitt et al, 1969), a term with sufficient ambiguity to gain the acceptance of those who thought these cells differentiated to a functional state in mammalian bone marrow and those who thought a mammalian equivalent of the bursa of Fabricius played a role in their differentiation.

A disquisition on suppressor T cells.

The main points that I have put forth are that: (1) suppressor T cell activity cannot be explained as simply being too much help; (2) feedback signals from target cells are of crucial importance in determining and maintaining the activity of suppressor T cells; (3) whenever T cells are triggered by antigen, suppression occurs. Immune responses only occur when countermanding signals are also generated. Both intrinsic and extrinsic adjuvanticity is the operational production of countermanding signals; (4) memory T cells are qualitatively different from normal T cells in their sensitivity to feedback signals and also in their susceptibility to suppression; (5) mature thymus dependent B cells cannot be rendered tolerant by the direct action of antigen, while immature and thymus independent B cells can; (6) the mechanism of suppression induced by exogenously administered antigens and that by normal differentiation products (i.e.: GVH; allotypes), is different; (7) generation of suppressor cells requires or results from complex interactions between subpopulations of cells, making it impossible under present conditions to determine which cell is doing what and to which; (8) further work is required before a full understanding of the importance, mechanism of action and other aspects of suppressor T cell function can be fully understood.

Activation of suppressor T cells by tumour cells and specific antibody

IMMUNOSUPPRESSION by passively administered antibody has long been known (see ref. 1 for review) and as antibody can cause enhancement of tumour growth2,3, particular attention has been paid to the role of antibody-mediated immunosuppression in tumour immunology. Hellstrom et al. have emphasised that blocking factors, most likely antigen-antibody complexes4, suppress cell-mediated immunity and thus play a major part in the progression of tumour growth5. Such blocking factors may be an important factor in the induction and/or maintenance of some forms of immunological tolerance6–8. But the mechanism remains obscure.

Immunologic Defenses against Metastases: Impairment by Excision of an Allotransplanted Lymphoma

Hamsters grafted with an allotransplantable lymphoma that does not metastasize develop a state of concomitant immunity which renders them refractory to reinoculation with cells of the same tumor. Removal of the tumor 7 days after transplantation rapidly leads to a decrease in immunity, the production of enhancing antibodies, and the appearance of metastatic deposits which are probably derived from preexisting tumor cells in the blood and lymphoid tissuces.

Histamine inhibition of the in vitro induction of cytotoxic T-cell responses☆

Addition of 10-3 to 10-6 M histamine (H)3 to mixed leukocyte cultures (MLCs) inhibited primary in vitro induction of cytotoxic T lymphocytes (CTLs) specific for either allogeneic or trinitrophenol-modified syngeneic target cells. The use of specific H agonists implicated H2 but not H1 receptor triggering in the mediation of these effects. Unlike in vivo-induced allogenic CTLs, the addition of H to assay culture failed to influence the effector function of in vitro-induced CTLs of either specificity. Kinetic studies showed that this difference might be due to loss of functional H receptors after the initiation of the in vitro MCL, and demonstrated that H interferes with an early event in the generation of CTLs. These data indicate that H receptors are not merely markers for CTL precursors, but that they are functional receptors, and suggest that H may play an important role in regulating both the generation and effector function of CTLs in vivo.

Ly-1 inducer and Ly-1,2 acceptor t cells in the feedback suppression circuit bear an I-J-subregion controlled determinant

An I-J-subregion controlled determinant is expressed on Ly-1 inducer and Ly-1,2 acceptor T cells in the feedback suppression circuit. Ly-1 T cells absorb the I-J antibody reactive with the Ly-1,2 acceptor T cell, suggesting that both inducer and acceptor T cells have the same 1-J determinant. Since less than 10 percent of Ly-1 or Ly-1,2 T cells are killed by anti-I-J plus complement treatment, the I-J determinant demarcates functionally distinct subsets of both the Ly-1 and Ly-1,2 T-cell sets. This I-J determinant is not expressed on a detectable number of Ly-1 helper T cells which induce B lymphocytes to produce anti-sheep red cell antibody in tissue culture.

Histamine inhibition of concanavalin A-induced suppressor T-cell activation

Abstract In vitro exposure to concanavalin A (Con A) results in the induction of T cells which suppress the in vitro generation of trinitrophenol (TNP)-modified self-specific cytotoxic T lymphocytes (CTLs). Such suppressor populations do not contain detectable CTLs or CTL precursors specific for TNP-modified syngeneic target cells. Histamine (10 −3 M ) inhibits both the DNA synthetic response and the generation of suppressor T lymphocytes induced by Con A.

T cells in a suppressor circuit and non-T: non-B cells bear different 1-J determinants

T cells involved in the generation of suppressor activity bear an I-J-subregion controlled determinant (e. g., J1) which is distinct from that (e. g., J1) found on non-T: non-13 accessory cells. T-cell subsets examined include Ly-1 inducer and Ly-1,2 acceptor cells which collaborate to generate suppressor activity in the in vitro sheep red blood cell antibody system. Non-T:non-B accessory cells examined include accessory cells involved in concanavalin-A induced, T-cell proliferative responses and in in vitro antibody responses to sheep red blood cells. These results provide evidence for serologic and genetic complexity of the I-J subregion of the murine H-2 gene complex.

Immunoregulation circa 1980: Some comments on the state of the art

Our knowledge of the cellular basis for immunoregulation has come a long way since 450 B.C. I choose that time as a starting point because, as far as I can tell, that was when the consideration that an immune response might exist was first documented.’ Thus, in the writings of Thucydides one can find comments on the possible role of the immune response in controlling the Black Death. Thucydides noted that the only people who could attend to subjects stricken by the plague were those who had previously had the disease and had survived it.’ No mechanism for this interesting observation was put forth at that time. Perhaps the problems the Athenians were having with the Spartans diverted money from basic research into the military budget. In any case, this observation of Thucydides was more buried in the literature than was the seminal article by Glick et al. on the effects of removal of the bursa of Fabricius from chickens, published in the journal Poultry Science. ’ The next major advance for which I can find documentation in western literature was made by industry rather than by academicians.’ The industry I refer to was the production and supply of subjects for Turkish harems. Not surprisingly, the market value on women being supplied to the harems was rather low if the women were to contract smallpox (veils to the contrary not withstanding). Thus, the parents of the potential harem maidens would pretreat their children with scabrous material obtained from cases of active smallpox. I can find no reference in the literature concerning the morbidity brought about by this treatment regimen but apparently those who failed to succumb to the disease truly developed resistance and thus could fetch premium prices on the open market.

Affinity-purified antigen-specific products produced by T cells share epitopes recognized by heterologous antisera raised against several different antigen-specific products from T cells

Heterologous antisera to murine or rat T-cell antigen-binding molecules (T-ABM) were raised in rabbits or sheep. The T-ABM used for immunization were purified by affinity for antigen and did not bear known immunoglobulin isotypes. T-ABM and anti-T-ABM were raised in three separate laboratories. Antisera to T-ABM were exchanged and tested for binding to T-ABM in three separate laboratories. Thus antisera to at least three distinct T-ABM were tested directly for binding to T-ABM or by adsorption of biological activity. Rabbit antisera to murine trinitrophenol (TNP)-specific T-ABM or rat AgB-specific T-ABM bound both murine or rat T-ABM, indicating evolutionary conservation of T-ABM. Similar results were found with sheep antisera to murine T-ABM. In addition, all heterologous anti-T-ABM antisera used bound murine T-ABM specific for TNP, 4-hydroxy-3-nitrophenyl acetate (NP), SRBC, or T-cell membrane proteins with similar structure. Thus, there is a commonality of antigenic determinants between various T-ABM and T-cell membrane homologues which may be T-cell surface receptors for foreign antigen.