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INDUCTION OF IgA EXPRESSION BY B‐CELLS RESPONSIVE TO THYMUS‐INDEPENDENT ANTIGENS

Thymus-independent antigens have been defined as those that can induce formation of specific antibodies in an athymic animal. This response is predominantly IgM or IgG, in vivo. We present evidence that the B-cell population responding to thymus-independent antigens is multipotential with respect to clonal isotype potential, and that this response may be influenced by external signals from T-cells and accessory cells. The frequency and isotype potential of antigen-sensitive cells was determined using the Klinman splenic fragment assay. Donor cells were injected intravenously into the tail veins of unprimed or carrier-primed, lethally irradiated recipients at limiting dilution. After 16 hours, recipient spleens were removed and diced; the fragments were distributed into microtiter plates, and challenged with antigen. Supernatants were collected and analyzed for specific antibody by radioimmunoassay. Thymus-independent antigens elicited predominantly IgM and IgG, immunoglobulins in the serum of mice when administered parenterally. In vitro Blymphocytes responsive to the thymus-independent antigens trinitrophenylated (TNP)-Ficoll, bacterial levan, or a pneumococcal vaccine, however, were able to stimulate clonal expansion and the heavy chain class switch, as judged by multiple isotype production by B-lymphocytes at a limiting dilution. The isotypes expressed in vitro included IgG,, IgG,, and IgA. In order to determine whether B-lymphocytes responsive to thymus-independent antigens could be affected by “bystander” effects, cultures stimulated with (TNP)-Ficoll or pneumococcal vaccine were costimulated with phosphocholinehemocyanin or hemocyanin (Hy). The irradiated recipients had been immunized with Hy in complete Freund’s adjuvant five to eight weeks previously to generate Hy-specific T-cell help. Also, treatment of the donor-cell inoculum with antiThy-1 plus complement followed by stimulation with levan in vitro was performed to assess any contribution of T-cells in the donor inoculum. Our data indicate that when “bystander” Hy-specific cells are stimulated, a decrease in the proportion of clones producing IgM is observed with an increase in the proportion expressing IgG and/or IgA; the greatest increase is seen in IgG,, IgG,, and IgA expression. Elimination of Thy-1 positive cells in the donor inoculum leads to an increase in IgM-producing clones and an accompanying effect of fewer clones expressing IgG, and clones producing IgA only. Antigenic determinants frequently associated with common gut flora are often carbohydrate moieties that induce a classic thymus-independent response in the mouse. We classify these as environmental antigens on the basis of the relatively high frequency of antigen-sensitive B-lymphocytes reactive to them in adult mice, and the high proportion of these cells in Peyer’s patches committed to generating clones exclusively expressing IgA. BALB/c mice, germfree for up to one year of life. have a low frequency of PC and inulin-reactive cells. Neonatal mice resemble germfree mice in their low numbers of inulin-reactive B-cells; however,