B cell immunopoiesis: visualizing the impact of CD40 engagement on the course of T cell-independent immune responses in an Ig transgenic system

This study tracks the fate of antigen-reactive B cells through follicular a nd extrafollicular responses and addresses the function of CD40 in these pr ocesses. The unique feature of this system is the use of transgenic B cells in which the heavy chain locus has been altered by site-directed insertion of a rearranged V-H DJ(H) exon such that they are able to clonally expand, isotype-switch and follow a normal course of differentiation upon immuniza tion. These lg transgenic B cells when adoptively transferred into non-tran sgenic (Tg) mice in measured amounts expanded and differentiated distinctiv ely in response to T cell-independent (Tl) or T cell-dependent (TD) antigen s. The capacity of these Tg B cells to faithfully recapitulate the humoral immune response to Tl and TD antigens provides the means to track clonal B cell behavior in vivo. Challenge with Tl antigen in the presence of agonist ic anti-CD40 mAb resulted in well-defined alterations of the Tl response. I n vivo triggering of Tg B cells with Tl antigen and CD40 caused an increase in the levels IgG produced and a broadening of the lg isotype profile, cha racteristics which partially mimic TD responses. Although some TD character istics were induced by Tl antigen and CD40 triggering, the Tg B cells faile d to acquire a germinal center phenotype and failed to generate a memory re sponse. Therefore, TD-like immunity can be only partially reconstituted wit h CD40 agonists and Tl antigens, suggesting that there are additional signa ls required for germinal center formation and development of memory.