When mouse bone marrow cells are mixed with cortisol-resistant thymocytes and stimulated in vitro with concanavalin A, the mitogenic response observed is much greater than additive, that is, it is synergistic. Between 94 and 96% of responding cells could be identified as T cells (Thy-1 positive) and of these, 79-100% derived from the cortisol-resistant thymocyte population, not from the bone marrow. Purified macrophages could not replace bone marrow; and marrow depleted of mature T or B cells worked as well as normal marrow. Thus, T and B cells and macrophages were ruled out as the synergizing cell of bone marrow. Nude spleen contained 10 times as many precursors of T cells as did nude marrow and was 10 times better at synergy with cortisol-resistant thymocytes. This implication of the pre-T cell as synergizer was supported by the finding that the synergistic activity of marrow was lost on preincubation, but maintained if the preincubation medium contained thymosin or cyclic AMP. Thus, the ability to enhance the response of relatively mature T cells to Con A is a property of pre-T cells. It is anticipated that this property will allow more detailed studies of T-cell precursor development in mice, and possibly in man.
The activity of.T lymphocyte precursors (pre-T cells) in the bone marrow of mice was measured by the concanavalin A response synergy assay. Pre-T cell levels were low in marrow of neonatally thymectomized mice and could be restored to control values by treatment in vivo with an extract of mouse thymus. Levels of activity were also low in aging mice and again could be restored by thymic extract treatment. The most profound fall with ang was in the proliferating pre-T cell compartment as detected bytritiated thymidine suicide; and this compartment was restored by thymic extract treatment. Irradiation to the thymus, with the bone marrow shielded, caused a fall in resting pre-T cells in the bone marrow and a concomitant rise in proliferating cells. These results are consistent with a model of control of pre-T cell maturation in which the thymus senses the number of developing iymphocytes within it and responds to a fall in this number by increasing production of hormone. The hormone acts on resting pre-T cells in the marrow, stimulating some of them to proliferate, leave the bone marrow, and repopulate the thymus.
After surface immunoglobulin-bearing (sIg+) cells are removed from mouse bone marrow on an anti-Ig immunoadsorbent column, precursors of bone marrow-derived (B) lymphocytes can be observed to differentiate in vitro. Expression of sIg occurs spontaneously on approximately 50% of the small lymphocytes during 3 days in culture. The rate of expression is accelerated by lipopolysaccharide (LPS), cyclic AMP, or the cyclic AMP phosphodiesterase inhibitor R020-1724; after 20 hr in culture approximately 35% of the small lymphocytes are sIg+ in induced cultures compared to 11% in controls. Acquisition of the ability to respond by proliferation to the mitogen LPS does not occur spontaneously in vitro but can be induced. Mitogen responsiveness in unfractionated bone marrow cells is increased by a 2-day preincubation with any of the inducing agents (cAMP, R020-1724, or LPS itself). However, anti-Ig column-passed marrow can be induced only with LPS or another mitogen, dextran sulfate, and this induction is prevented by BUdR and light. We propose that immature B cells express sIg, and then must undergo further differentiation, possibly linked to cell division, before becoming responsive to LPS. Agents that raise intracellular cAMP accelerate expression of sIg and mitogen responsiveness in two distinct cell populations, and may do so by accelerating new genetic programs after determination events.
The IgG1 and IgE homocytotropic antibody responses of LAF1 and C3H mice to timothy pollen antigens are defined. Both mouse strains responded to low doses of crude timothy pollen extract (WST) or a major antigen of timothy pollen coupled to a purified fraction of Ascaris suum (Antigen B-Ascaris). Titers in LAF1 mice were greater than those in C3H mice. Regardless of the immunogen, antigen B was the major determinant recognized by the homocytotropic antibodies; PCA titers with WST or antigen B for challenge were equivalent and PCA activity could be inhibited by antigen D, a dialyzable fraction of timothy pollen possessing the antigen B determinant in monovalent form. The possible usefulness of antigen D for in vivo and in vitro studies of specific immune suppression of cellular activity is discussed.
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