Th2-Dependent B Cell Responses in the Absence of CD40-CD40 Ligand Interactions

Abstract

CD40 is thought to play a central role in T cell-dependent humoral responses through two distinct mechanisms. CD4+ T helper cells are activated via CD40-dependent Ag presentation in which CD80/CD86 provides costimulation through CD28. In addition, engagement of CD40 on B cells provides a direct pathway for activation of humoral responses. We used a model of adenovirus-mediated gene transfer of β-galactosidase (lacZ) into murine lung to evaluate the specific CD40-dependent pathways required for humoral immunity at mucosal surfaces of the lung. Animals deficient in CD40L failed to develop T and B cell responses to vector. Activation of Th2 cells, which normally requires CD40-dependent stimulation of APCs, was selectively reconstituted in CD40 ligand-deficient mice by systemic administration of an Ab that is agonistic to CD28. Surprisingly, this resulted in the development of a functional humoral response to vector as evidenced by formation of germinal centers and production of antiadenovirus IgG1 and IgA that neutralized and prevented effective readministration of vector. The CD28-dependent B cell response required CD4+ T cells and was mediated via IL-4. These studies indicate that CD40 signals to the B cells are not necessary for CD4+ Th2 cell-dependent humoral responses to be generated.

Differential Requirements for Expression of CD80/86 and CD40 on B Cells for T-Dependent Antibody Responses In Vivo

“…Our finding that CD40 expression on B cells is necessary for B cell responses runs counter to a recent study (35) in which use of an agonistic Ab to CD28 was able to restore a Th2-dependent B cell response to an adenovirus vector in CD40L KO mice. The authors of this study concluded that direct CD40 signaling to B cells during a Th2-TD response is not required if Th cell function is activated.…”

Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation

“…In support of this hypothesis are previous reports of IgA synthesis in vertebrates by commensal bacteria in the absence of T cells, presumably through stimulation of B cells through toll-like receptors (14). Furthermore, serum IgA has also been observed in humans with CD40L deficiency and can be induced in CD40L -/-mice in the absence of CD40 stimulation (15,16). Taken together these observations suggest a CD40-independent mechanism for serum IgA in some patients with XHM-ED.…”

Gut IgA Class Switch Recombination in the Absence of CD40 Does Not Occur in the Lamina Propria and Is Independent of Germinal Centers

“…On the other, the transfer of B1 cells without T cells to SCID mice failed to produce significant gut IgA, arguing in favor of T cell involvement (7,12,14). Such involvement may, however, not require cognate T-B cell interactions but may still depend on CD40L expression or other factors surface expressed or released by activated T cells (15,16). Another site of potential interest for IgA B cell development is the large number of isolated lymphoid follicles (ILF) that are scattered along the antimesenteric border of the small intestine (8,17).…”