Separation of mouse spleen cells by passage through columns of sephadex G-10.

Publisher Summary This chapter discusses the intimate mechanisms of the regulation of antibody responses by T cells, the significance of these phenomena for the regulatory processes of the immune system, and their possible implication for the pathogenesis of various immunopathological states. The chapter adheres to popular terminology to refer to the two distinct classes of immunocompetent lymphocytes—T cells and B cells. The T cells are lymphocytes that have differentiated under the influence of the thymus and are responsible for mediating cellular immune reactions—such as delayed hypersensitivity and transplantation reactions. These cells participate in the development of humoral immunity but are not capable of secreting humoral antibodies. Because T cells stimulated by antigen respond by a clonal expansion and differentiation; and by being activated to perform their specific function, the former is elected as “educated T cells” and the latter as “activated T cells.” Activated T cells may result from stimulation by agents other than specific antigen. The B cells are lymphocytes that have differentiated under the influence of the bursa or its analog in mammals and ultimately become the effector cells in humoral immunity by the virtue of synthesizing and secreting immunoglobulin antibodies.

The regulatory influence of activated T cells on B cell responses to antigen.

Brain-associated theta antigen: reactivity of rabbit anti-mouse brain with mouse lymphoid cells.

Publisher Summary Paralysis is seriously considered only in the “two specific signal” hypothesis by postulating that the first signal, generated by the combination of antigen with the specific receptor, results in tolerance rather than induction, except if the cell is simultaneously exposed to the second specific signal, generated by the recognition of the antigen by associative antibody. This model of associative recognition is designed in order to explain self-nonself discrimination and denies the existence of truly thymus-independent (TI) antigens as well as the possibility of triggering B cells by any mechanism not involving the first specific signal. The main general conclusion concerning induction of paralysis by TI antigens is that specific B cells are turned off at higher concentrations of the TI antigen than those causing activation. TI antigens do induce specific B cells directly and one cannot exclude that at least some of them also activate other cell types, including T cells, nor that some or possibly all of them interact with macrophages. It is suggested that the effects on other cell types represent trivial or optimizing events on top of the basic, fundamentally effective mechanism of direct B-cell activation. All TI antigens are competent to activate B cells polyclonally and this nonspecific property seems to be responsible for induction of specific cells. The inactivation of competent specific cells is also a result of the interaction between nonspecific surface receptors and the competent ligand.

Thymus-independent B-cell induction and paralysis.

The constitutive culture supernatant (SN) of the macrophage tumor line P388D1 (P388 SN) and the concanavalin A (Con A)-induced culture supernatant of the T cell hybridoma FS6-14.13 (FS6 Con A SN) were shown to contain nonspecific factors capable of inducing increased Ia expression by normal resting B cells in a dose-dependent manner. In six consecutive experiments the relative increase in Ia expression induced by P388 SN was 4.9 +/- 0.9, with FS6 Con A SN 10.7 +/- 1.5, and with a combination of both preparations 13.0 +/- 1.7. This increase in Ia expression was observed to occur in virtually all the B cells, reaching maximum levels within 24 h of culture. The interleukin-induced increase in B cell Ia expression occurred in the absence of ancillary signals provided by ligand-receptor Ig cross-linking and despite the fact that virtually all the control B cells, cultured in the absence of factors, remained in G0. These results suggest that functional receptors for at least some interleukins are expressed on normal resting B cells and their effects can be manifest in the absence of additional activating signals. The increased Ia expression induced by the nonspecific factor preparations was shown to be correlated with enhanced antigen-presenting capacity by the B cells to T cell hybridomas. The nature of the interleukins responsible for these effects remains to be definitively determined, however, the activity of FS6 Con A SN was shown to correlate with B cell growth factor activity and increased B cell Ia expression was not observed using interleukin 2 (IL-2) or interferon-gamma, prepared by recombinant DNA technology.

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Interleukin-induced increase in Ia expression by normal mouse B cells.

Cytotoxic antiserum to theta antigen reduces the capacity of mouse spleen cells to generate direct and indirect plaque-forming cells to sheep erythrocytes in vitro but does not affect plaque-forming cells, their precursors, or hemopoietic stem cells. The response of spleen cells treated with antiserum to theta antigen is restored by thymus cells incubated in vivo with sheep erythrocytes.

https://science.sciencemag.org/content/sci/170/3963/1215.full.pdf

Cell Interaction in an Immune Response in vitro: Requirement for Theta-Carrying Cells

The anti-Lac B precursor cells from BALB/c (H-2) d mice which survive cytotoxic treatment with anti-Ia k and complement will respond to Lac-KLH in culture, but require more KLH helper T cells than unselected B cell populations or B cells surviving anti-Ig killing. These findings are not explainable by the classical Poisson assumption of a constant target of T-B ionteraction. We propose a T-B interaction theory with variable Ia target on the B cell surface. The theory quantitatively predicts the observed dose response relationships, and implies that Ia molecules on B cells are cell interaction structures.

Expression and function of i region products on immunocompetent cells. II. I region products in t-b interaction.

Both helper and suppressor activities for an in vitro IgG anti-hapten (Lac) response to Lac-HRBC were demonstrated in the same population of carrier (HRBC)-primed spleen cells. The relative radiosensitivity of suppressor activity permitted the selective removal of suppression and the demonstration of help. Both activities appear to be T cell-dependent and antigen-specific. Dilution analysis showed that help and suppression are mediated by distinct populations of cells.

Coexistence of helper and suppressor activities in carrier-primed spleen cells.

We have examined the cytotoxic activity of anti-Iak serum and complement on various immune functions of BALB/c (H-2d) cells. Since the cytotoxic action of this antiserum on H-2d cells defines specificity Ia.7, an I-C region product, we have looked at the selective expression of this antigen. We have mainly used the in vitro anti-Lac2 response to study the cells involved in the induction and regulation of antibody. The data presented here show that Ia.7 is present on both IgM and IgG precursor B cells and in lesser amounts on plaque-forming cells. The antiserum also recognizes with less efficiency a product on specific T suppressor cells, which is possibly coded for by the adjacent I-J subregion. Both fluorescence and functional tests indicate the absence of Ia.7 on macrophages. It is also lacking on T helper cells. When we tested the antiserum on the in vitro cytotoxic responses to alloantigens, we found that neither T effector cells nor their precursors were affected.

Expression and Function of I Region Determinants on Immunocompetent Cells I. Selective Expression of I-C Region Determinants on Immune Cells

The anti-Lac B precursor cells from Balb/c mice which survive cytotoxic treatment with anti-Ia k will respond to Lac-KLH in culture but require more KLH helper T cells than the untreated B cell population. These findings are not explainable by the simple Poisson assumption of a constant target of T-B interaction. We propose an interaction theory with variable Ia target on the B cell surface. The theory quantitatively predicts the observed dose-response relationships, and implies a central role for Ia in T-B interaction.

Eva L. Chan

Papers

Cell Interaction in an Immune Response in vitro: Requirement for Theta-Carrying Cells

Expression and function of i region products on immunocompetent cells. II. I region products in t-b interaction.

Coexistence of helper and suppressor activities in carrier-primed spleen cells.

Expression and Function of I Region Determinants on Immunocompetent Cells I. Selective Expression of I-C Region Determinants on Immune Cells

ON THE ROLE OF Ia IN B-T CELL INTERACTION