“Negative Vaccination” by Specific CD4(+) T Cell Tolerisation Enhances Virus-Specific Protective Antibody Responses

BACKGROUND: Cooperation of CD4(+) T helper cells with specific B cells is crucial for protective vaccination against pathogens by inducing long-lived neutralizing antibody responses. During infection with persistence-prone viruses, prolonged virus replication correlates with low neutralizing antibody responses. We recently described that a viral mutant of lymphocytic choriomeningitis virus (LCMV), which lacks a T helper epitope, counterintuitively induced an enhanced protective antibody response. Likewise, partial depletion of the CD4(+) T cell compartment by using anti-CD4 antibodies enhanced protective antibodies. PRINCIPAL FINDINGS: Here we have developed a protocol to selectively reduce the CD4(+) T cell response against viral CD4(+) T cell epitopes. We demonstrate that in vivo treatment with LCMV-derived MHC-II peptides induced non-responsiveness of specific CD4(+) T cells without affecting CD4(+) T cell reactivity towards other antigens. This was associated with accelerated virus-specific neutralizing IgG-antibody responses. In contrast to a complete absence of CD4(+) T cell help, tolerisation did not impair CD8(+) T cell responses. CONCLUSIONS: This result reveals a novel “negative vaccination” strategy where specific CD4(+) T cell unresponsiveness may be used to enhance the delayed protective antibody responses in chronic virus infections.