Biomedical subjects
Publications and source records attributed to K Shortman.
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Quantitative studies on B cells require a direct assay for antibody-forming cell (AFC) progenitor function, in which the number of AFC produced bears a simple, linear arithmetic relationship to the number of progenitors present. This might be expected under conditions where helper T-cell and accessory cell requirements are by-passed, or provided in excess. This possibility has been tested using as antigen the hapten NIP (4-hydroxy-3-iodo-5-nitrophenylacetic acid) on the carrier POL (polymerized bacterial flagellin), in adoptive transfer of normal and nude mouse spleen cells to irradiated recipients, and in cell culture. Primary and secondary IgM responses to this antigen are "T cell-independent'. The secondard IgG response is T cell-dependent but this function can be provided by 'carrier-primed' irradiated recipients. However in no case did the cell dose response curve show a linear, arithmetic relationship between cells transferred or cultured, and AFC produced. If less than 10 X 10(6) cells were adoptively transferred or cultured, a sigmoid curve was obtained, approximately linear with a slope of around 1-6 on a log-log scale. In adoptive transfer, a plateau was then seen above 10 X 10(6) cells, followed by a second sharp rise beginning around 15 X 10(6) cells. Addition of irradiated spleen cells as 'fillers' to maintain cell numbers constant produced a linear (arithmetic scale) dose response curve for the primary IgM responses, both adoptive and in culture. Lipopolysaccharide injection of recipients also produced linear regions in the adoptive transfer system. These techniques provide more direct, quantitative assay systems for the primary IgM responses to this antigen. However, arithmetic linear cell dose response curves were still not obtained for the secondary IgG responses, using irradiated filler cells.
Distinct sub-populations of B lymphocytes may be fractionated by passage through glass-bead columns, due to a temperature-independent adherence of certain cells. The relative adherence properties of AFC-progenitors from spleens of primed or unprimed CBA mice were compared with an adoptive immune assay employing as antigen the hapten NIP on the carrier polymerized flagellin, under conditions where T lymphocytes did not limit the response. The AFC-progenitors for an anti-NIP IgM response from unprimed mice, whether conventional, germ-free, or athymic were more adherent than the majority of cells in the spleen. The AFC-progenitors for an IgG response from hapten-primed mice were less adherent that the majority of spleen cells. The results indicate that there are sub-classes of AFC-progenitors, differing in surface properties and probably corresponding to differences between the "antigen-inexperienced" and the "memory" B cell populations.
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Equilibrium density separation on continuous albumin gradients was used to separate and characterise the T cells responding by proliferation to both syngeneic and allogeneic stimulating cells in the one-way mixed leucocyte reactions (MLR). In CBA mouse spleen both light and dense T cells were capable of responding in an allogeneic MLR. No T cells responding to stimulation be syngeneic B lymphocytes could be isolated from adult or 7-day CBA mouse spleen. In adult CBA mouse thymus, cells responding to allogeneic stimuli were enriched in the light density region, along with the low theta subpopulation. Self-reactive cells, responding with proliferation when cultured with syngeneic adult CBA splenic lymphocytes, and found in adult and 4-day CBA mouse thymus, were also enriched in the light density zones. However, in adult thymus syngeneic MLR reactivity was also found in the dense zones, and the density distribution profiles of total syngeneic MLR responding cells revealed a series of peaks extending over the whole density range. It was suggested that these syngeneic MLR responders undergo a complete maturation process, including progressive density increases, within the thymus gland. Such a sterile differentiation pathway could be a censorship process, leading to death of self-reactive cells within the thymus.
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Thymus cells from CBA and BALB/c mice are stimulated by syngeneic peripheral lymphoid cells in a "one-way" mixed lymphocyte reaction. The stimulating cell appears to be a mature B cell. Spleen cells from neonatal mice and thymus cells or bone marrow cells from adult mice are not able to induce DNA synthesis in syngeneic thymus cells, although they stimulate significantly allogeneic thymocytes. The ability of peripheral B cells to serve as stimulating cell in a syngeneic reaction develops with the age of the animal. The marginal stimulation of syngeneic thymus cells when 90% pure peripheral T cells were used as stimulating cells indicated that T cells alone were ineffective in stimulating in syngeneic mixed lymphocyte reaction. However they stimulated effective allogeneic thymocytes. On a cell-to-cell basis, light density splenic lymphocytes stimulated both syngeneic and allogeneic thymocytes better than did more dense lymphocytes. The data obtained suggest that stimuli other than those responsible for allogeneic stimulation induce proliferation of syngeneic thymus cells under identical culture conditions.
Density distribution analysis in continuous gradients of albumin has been used to study the development of cytotoxic lymphocytes (CL), to separate and characterize the progenitors of CL, and to determine their relationship to subpopulations of T cells. CL progenitors in the thymus were a homogeneous, medium-density population, distinct from the typical, dense, thymus small-lymphocyte. Activity seemed to be associated with one minor subpopulation of cells with surface antigenic properties characteristic of peripheral T cells (high levels of H-2 antigen, low levels of theta-antigen). CL progenitors in the spleen differed from those in the thymus and normally had the high buoyant density of typical small T lymphocytes. In states of antigenic stimulation, some lighter-density CL progenitors were found in the spleen. The buoyant density of the CL population developing in the spleens of immunized animals showed progressive changes with time. Early, "immature" CL had the light-density characteristics of large, activated lymphocytes. As the response developed, the density of the CL population increased, and finally approached that of CL progenitors and of typical small lymphocytes. The data suggest that density subpopulations of T cells represent stages in the development of immunocompetent cells. Possible differentiation pathways of T lymphocytes in the thymus and in the spleen are discussed.
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