"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.


RESULTS
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.
Lang
Karl S
KS
Institute of Experimental Immunology, Department of Pathology, University Hospital Zurich, Zurich, Switzerland. karlslang@gmail.com
Hegazy
Ahmed N
AN
Lang
Philipp A
PA
Eschli
Bruno
B
Löhning
Max
M
Hengartner
Hans
H
Zinkernagel
Rolf M
RM
Recher
Mike
M
D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009500:Neutralization Tests
D000914:Antibodies, Viral