Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities.
Antibody responses are critical components of protective immune responses to many pathogens, but parameters determining which proteins are targeted remain unclear. Vaccination with individual MHC-II-restricted vaccinia virus (VACV, smallpox vaccine) epitopes revealed that CD4(+) T cell help to B cells was surprisingly nontransferable to other virion protein specificities. Many VACV CD4(+) T cell responses identified in an unbiased screen targeted antibody virion protein targets, consistent with deterministic linkage between specificities. We tested the deterministic linkage model by efficiently predicting new vaccinia MHC II epitopes (830% improved efficiency). Finally, we showed CD4(+) T cell help was limiting for neutralizing antibody development and protective immunity in vivo. In contrast to the standard model, these data indicate individual proteins are the unit of B cell-T cell recognition for a large virus. Therefore, MHC restriction is a key selective event for the antiviral antibody response and is probably important for vaccine development to large pathogens.
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, CA 92037, USA.
Alessandro
A
Sette
Magdalini
M
Moutaftsi
Juan
J
Moyron-Quiroz
Megan M
MM
McCausland
D Huw
DH
Davies
Robert J
RJ
Johnston
Bjoern
B
Peters
Mohammed
M
Rafii-El-Idrissi Benhnia
Julia
J
Hoffmann
Hua-Poo
HP
Su
Kavita
K
Singh
David N
DN
Garboczi
Steven
S
Head
Howard
H
Grey
Philip L
PL
Felgner
Shane
S
Crotty
D019264:Adoptive Transfer; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000276:immunology*; D000918:Antibody Specificity; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009500:Neutralization Tests; D012900:Smallpox Vaccine / Q000276:immunology* / Q000378:metabolism; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D014616:Vaccinia virus / Q000276:immunology*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; D012900:Smallpox Vaccine