"Negative vaccination" by specific CD4 T cell tolerisation enhances virus-specific protective antibody responses

• Published in: PloS one Vol. 2; no. 11; p. e1162
• Main Authors: Lang, Karl S, Hegazy, Ahmed N, Lang, Philipp A, Eschli, Bruno, Löhning, Max, Hengartner, Hans, Zinkernagel, Rolf M, Recher, Mike
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.11.2007; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; AIDS; Amino Acid Sequence; Animals; Antibodies; Antibodies, Viral - biosynthesis; Antibodies, Viral - immunology; Antibody response; Antigens; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Cell Separation; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Glycoproteins; Helper cells; Hepatitis; HIV; Human immunodeficiency virus; Immune Tolerance; Immunoglobulin G; Immunoglobulins; Immunology; Immunology/Immune Response; Infections; Infectious Diseases; Infectious Diseases/HIV Infection and AIDS; Infectious Diseases/Viral Infections; Lymphocytes; Lymphocytes B; Lymphocytes T; Major histocompatibility complex; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Neutralization Tests; Neutralizing; Pathology; Peptides; Rodents; T cell receptors; Vaccination; Viral infections; Virology/Vaccines; Viruses; Switzerland; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0001162

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. 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. 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.