Recombinant Rabies Virus Overexpressing OX40-Ligand Enhances Humoral Immune Responses by Increasing T Follicular Helper Cells and Germinal Center B Cells

Abstract

Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role in the T cell-dependent humoral immune responses through T-B cell interaction. In this work, a recombinant RABV overexpressing mouse OX40L (LBNSE-OX40L) was constructed, and its effects on immunogenicity were evaluated in a mouse model. LBNSE-OX40L-immunized mice generated a larger number of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs) than the parent virus LBNSE-immunized mice. Furthermore, LBNSE-OX40L induced significantly higher levels of virus-neutralizing antibodies (VNA) as early as seven days post immunization (dpi), which lasted for eight weeks, resulting in better protection for mice than LBNSE (a live-attenuated rabies vaccine strain). Taken together, our data in this study suggest that OX40L can be a novel and potential adjuvant to improve the induction of protective antibody responses post RABV immunization by triggering T cell-dependent humoral immune responses, and that LBNSE-OX40L can be developed as an efficacious and nonpathogenic vaccine for animals.

Overexpression of Interleukin-33 in Recombinant Rabies Virus Enhances Innate and Humoral Immune Responses through Activation of Dendritic Cell-Germinal Center Reactions

“…The interaction between mature DCs and T cells or B cells is the basis for inducing the acquired immune response [27]. Previous studies have shown that rRABV expressing the stimulating factor of DCs can activate host innate immunity by recruiting and activating DCs, rapidly inducing a high level of early virus neutralizing antibody (VNA) production and improving its immunogenicity [28,29]. However, the production of antibody is slow and transient in existing studies.…”

Strategy construction to minimize the limitation of respiratory viral vaccine development

“…59,60 Fascinatingly, CD4 T cells that cannot receive OX40 signals when decreased activity of Akt (protein kinase B) and NF-κB1 has occurred and forced expression of an active version of Akt restored defective expansion and survival of OX40deficient T cells when responding to antigen. 35 Antigenindependent signal could be provided by sources of OX40L which might include LTi cells, B cells, and responding T cells themselves for the support of T cell survival at the late effector phase of immune responses. Simultaneously it can visualize that in presence of antigen ligation of OX 40 provides additional signals and the signal are completely dependent on TCR signaling.…”

The OX40/OX40L Axis Regulates T Follicular Helper Cell Differentiation: Implications for Autoimmune Diseases

“…OX40L was found to be expressed in the GCs and surrounding areas, suggesting that OX40/OX40L signaling may play a role in formation of the GC. Li Y et al constructed a recombinant rabies virus (RABV) mouse model (LBNSE-OX40L) which overexpressed OX40L and found that Tfh cells and GC-B cells significantly increased after RABV infection ( 74 ). Deletion of OX40L in B cells in the SLE mouse model resulted in an improved disease index and a decreased number of plasma cells and GC-B cells ( 75 ).…”