The Early Protective Thymus-Independent Antibody Response to Foot-and-Mouth Disease Virus Is Mediated by Splenic CD9⁺B Lymphocytes

Abstract

Infection of mice with cytopathic foot-and-mouth disease virus (FMDV) induces a rapid and specific thymus-independent (TI) neutralizing antibody response that promptly clears the virus. Herein, it is shown that FMDV-infected dendritic cells (DCs) directly stimulate splenic innate-like CD9؉ B lymphocytes to rapidly (3 days) produce neutralizing anti-FMDV immunoglobulin M antibodies without T-lymphocyte collaboration. In contrast, neither follicular (CD9 ؊ ) B lymphocytes from the spleen nor B lymphocytes from lymph nodes efficiently respond to stimulation with FMDV-infected DCs. The production of these protective neutralizing antibodies is dependent on DC-derived interleukin-6 (IL-6) and on CD9؉ cell-derived IL-10 secretion. In comparison, DCs loaded with UV-inactivated FMDV are significantly less efficient in directly stimulating B lymphocytes to secrete TI antibodies. A critical role of the spleen in the early production of anti-FMDV antibodies in infected mice was also demonstrated in vivo. Indeed, either splenectomy or functional disruption of the marginal zone of the spleen delays and reduces the magnitude of the TI anti-FMDV antibody response in infected mice. Together, these results indicate that in addition to virus localization, the FMDV-mediated modulation of DC functionality is a key parameter that collaborates in the induction of a rapid and protective TI antibody response against this virus.Experimental infection of mice with serotype O of foot-andmouth disease virus (FMDV), the prototypic member of the genus Aphthovirus of the family Picornaviridae, causes a subclinical infection characterized by viral replication in the pancreas and a viremia that lasts for 48 to 72 h (14, 17). At this time, concurrently with the appearance of serum neutralizing antibodies, the virus is cleared from circulation (8, 17).The humoral immune response against infectious FMDV proceeds in two phases: an early thymus-independent (TI) phase, involved in viral clearance, and a late thymus-dependent (TD) memory phase (8,60). A similar type of response has been described for other viruses such as vesicular stomatitis virus (VSV) (5, 58). We have recently shown that during the early phase of the response against infectious FMDV, there is a transient but generalized suppression of TD responses (51). This effect is mediated, at least in part, by the downregulation of major histocompatibility complex class II and CD40 molecules on dendritic cells (DCs) and by the production of interleukin-10 (IL-10) by splenocytes (51). In contrast, the antibody response against UV-inactivated FMDV (UV-FMDV) proceeds as a typical TD response. Thus, it exhibits a delayed induction (ϳ1 week). Moreover, the antibody isotypes elicited by the inactivated virus are different from those induced by infectious FMDV (52).DCs are potent stimulators of T-cell responses (56). In addition, DCs also have the ability to influence B-cell functionality by inducing isotype switching, differentiation towards the plasma cell, and antibody secretion (16). The stimulati...

Foot-and-Mouth Disease Virus Can Induce a Specific and Rapid CD4+T-Cell-Independent Neutralizing and Isotype Class-Switched Antibody Response in Naïve Cattle

“…These results have been confirmed in vitro in a mouse model in which FMDV-infected dendritic cells could directly stimulate B lymphocytes to secrete FMDV-specific IgM, but T-cell help was required to induce class switching toward IgG (50). Comparison of the kinetics of the FMDV-specific antibody response of experiment 1 and 2 animals over time did not reveal any statistically significant differences between the depleted groups and the control MAb-treated groups.…”

Co-inoculation of baculovirus and FMDV vaccine in mice, elicits very early protection against foot and mouth disease virus without interfering with long lasting immunity

“…The infection is well characterized and includes viral replication in the pancreas, without clinical symptoms [10,18]. Despite the differences regarding infection and symptomatology between mice and natural hosts, a number of similarities have been established, for example: the main role of Abs in resolving the infection [10,[19][20][21]; the life-long immunity after infection [22]; the T-independence of the immune response [19,23]; the key role for DC-secreted IL10 in FMDV-mediated immunosuppression [24][25][26]; etc. In addition, we have obtained preliminary data indicating that protection against viral challenge in adult BALB/c mice inoculated with commercial vaccines correlates with protection in cattle [13].…”

Immunosuppressive drugs have different effect on B lymphocyte subsets and IgM antibody production in immunized BALB/c mice

“…It is now known that B cells are divided into B-1 and B-2 or conventional B lymphocytes according to phenotype, tissue distribution and production of natural or polyreactive antibodies B-1 lymphocytes are involved in the early humoral response to pathogens, producing low affinity polyspecific IgM antibodies which are highly efficient in limiting infection by viruses or bacteria [1]. The role of polyreactive IgM antibodies in the immediate defence against systemic bacterial infection has been demonstrated in mice [2].…”