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.
Sette
Alessandro
A
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology (LIAI), La Jolla, CA 92037, USA.
Moutaftsi
Magdalini
M
Moyron-Quiroz
Juan
J
McCausland
Megan M
MM
Davies
D Huw
DH
Johnston
Robert J
RJ
Peters
Bjoern
B
Rafii-El-Idrissi Benhnia
Mohammed
M
Hoffmann
Julia
J
Su
Hua-Poo
HP
Singh
Kavita
K
Garboczi
David N
DN
Head
Steven
S
Grey
Howard
H
Felgner
Philip L
PL
Crotty
Shane
S
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