Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand

Abstract

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L, is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L monoclonal antibody, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-immunoglobulin (Ig)M stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice engendered apparent suppression of the recall reaction of T cells primed with both protein antigens and alloantigens and a significant reduction in keyhole limpet hemocyanin–specific IgG production. The impaired T cell priming was also accompanied by a concomitant reduction of both T helper type 1 (Th1) and Th2 cytokines. Furthermore, antigen-presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.

Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells

“…The generation of protective Th1 inflammatory CD4 T cell responses in C57BL/6 mice is also independent of OX40 signaling. This is somewhat contradicted by Murata et al 10, who show reduced production of the Th1 cytokine, IFN-γ, in OX40L-deficient mice. I think the confusion arises because Murata et al fail to distinguish Th1 CD4 help for B cells and Th1 CD4 help for inflammatory responses.…”

“…The experimental data of Murata et al 10 indicate that this might be so. If confirmed, it would be very interesting to define the cytokines and chemokine receptors expressed by these CD4 T cell subsets.…”

“…OX40 and CD28 signals are highly synergistic for CD4 T cell proliferation and survival 9. In this issue, Murata et al 10 report that OX40L-deficient mice have impaired CD4 T cell priming. In contrast, constitutive expression of OX40L on DCs 3 is associated with the opposite phenotype, with increased numbers of activated/memory CD4 T cells 6.…”

“…These papers suggest that Th1 and Th2 CD4 B cell help is primed by different DC subsets. However, Murata et al 10 have not examined an inflammatory CD4 response, so on the available data they cannot conclude that OX40 signals promote inflammatory Th1 CD4 T cells.…”

“…Murata et al 10 have looked at day 9 recall CD4 responses when the majority of primed CD4 T cells in normal mice are “helping” B cells in GCs. The in vitro CD4 recall response from T cells primed in OX40L-deficient mice hardly depends on the expression of OX40L upon restimulating APCs (Murata et al, compare Figure 6 A and Figure 6 B).…”