IL-2 and a contact-mediated signal provided by TCRαβ⁺ or TCR-γδ⁺ CD4⁺ T cells induce polyclonal Ig production by committed human B cells: Enhancement by IL-5, specific inhibition of IgA synthesis by IL-4

To study the role of T cells in T-B cell interactions resulting in isotype production, autologous purified human splenic B and T cells were cocultured in the presence of IL-2 and Con A. Under these conditions high amounts of IgM, IgG, and IgA were secreted. B cell help was provided by autologous CD4⁺ T cells whereas autologous CD8⁺ T cells were ineffective. Moreover, CD8⁺ T cells suppressed Ig production when added to B cells cocultured with CD4⁺ T cells. Autologous CD4⁺ T cells could be replaced by allogeneic activated TCRγδ,CD4⁺ or TCRαβ,CD4⁺ T cell clones with nonrelevant specificities, indicating that the TCR is not involved in these T-B cell interactions. In contrast, resting CD4⁺ T cell clones, activated CD8⁺, or TCRγδ,CD4^-,CD8^- T cell clones failed to induce IL-2-dependent Ig synthesis. CD4⁺ T-B cell interaction required cell-cell contact. Separation of the CD4⁺ T and B cells by semiporous membranes or replacement of the CD4⁺ T cells by their culture supernatants did not result in Ig synthesis. However, intact activated TCRαβ or TCRγδ,CD4⁺ T cell clones could be replaced by plasma membrane preparations of these cells. Ig synthesis was blocked by mAb against class II MHC and CD4. These data indicate that in addition to CD4 and class II MHC Ag a membrane-associated determinant expressed on both TCRαβ or TCRγδ,CD4⁺ T cells after activation is required for productive T-B cell interactions resulting in Ig synthesis. Ig production was also blocked by mAb against IL-2 and the IL-2R molecules Tac and p75 but not by anti-IL-4 or anti-IL-5 mAb. The CD4⁺ T cell clones and IL-2 stimulated surface IgM^-IgG⁺ and IgM^-IgA⁺, but not IgM⁺IgG^- or IgM⁺IgA^- B cells to secrete IgG and IgA, respectively, indicating that they induced a selective expansion of IgG- and IgA-committed B cells rather than isotype switching in Ig noncommitted B cells. Induction of Ig production by CD4⁺ T cell clones and IL-2 was modulated by other cytokines. IL-5 and transforming growth factor-β enhanced, or blocked, respectively, the production of all isotypes in a dose-dependent fashion. Interestingly, IL-4 specifically blocked IgA production in this culture system, indicating that IL-4 inhibits only antibody production by IgA-committed B cells.