B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin α-dependent fashion

Lymphotoxin (LT)alpha is expressed by activated T cells, especially CD4(+) T helper type 1 cells, and by activated B and natural killer cells, but the functions of this molecule in vivo are incompletely defined. We have previously shown that follicular dendritic cell (FDC) clusters and germinal centers (GCs) are absent from the peripheral lymphoid tissues of LT alpha-deficient (LT alpha(-/-)) mice. LT alpha(-/-) mice produce high levels of antigen-specific immunoglobulin (Ig)M, but very low levels of IgG after immunization with sheep red blood cells. We show here that LT alpha-expressing B cells are essential for the recovery of primary, secondary, and memory humoral immune responses in LT alpha(-/-) mice. It is not necessary for T cells to express LT alpha to support these immune functions. Importantly, LT alpha-expressing B cells alone are essential and sufficient for the formation of FDC clusters. Once these clusters are formed by LT alpha-expressing B cells, then LT alpha-deficient T cells can interact with B cells to generate GCs and productive class-switched antibody responses. Thus, B cells themselves provide an essential signal that induces and maintains the lymphoid microenvironment essential for GC formation and class-switched Ig responses.