Impaired germinal centre formation and humoral immune response in the absence of CD28 and interleukin-4.

The generation of an optimal humoral immune response requires fully activated T-cells. For complete activation at least two signals are needed. The first one is an antigen dependent one via the T cell receptor, the second one is a costimulatory signal which can be delivered by the CD28 molecule after binding to CD80 (B7.1) or CD86 (B7.2). Fully activated T helper cells are competent to deliver help to B-cells by secreting cytokines (e.g. interleukin (IL)-4) or up-regulating CD40 ligand for proliferation and differentiation of B cells. These interactions mainly take place in germinal centres (GC) that arise after antigen stimulation in B cell-follicles of peripheral lymphatic tissues and are the sites of massive B-cell proliferation, affinity maturation and class switch. The roles of CD28 and IL-4 were investigated in GC formation and antibody production. A markedly diminished humoral immune response was observed in IL-4(-/-) xCD28(-/-) mice whereas in CD28(-/-) and IL-4(-/-) mice the defect was less severe. Especially the formation of germinal centres was significantly reduced in CD28(-/-) or IL-4(-/-) mice and almost undetectable in IL-4(-/-) xCD28(-/-) mice. Taken together these data indicate that CD28 and IL-4 are synergistically involved in GC formation and immunoglobulin production.