title: Unlinked memory helper responses promote long-lasting humoral alloimmunity.
abstract: Essential help for long-lived alloantibody responses is theoretically provided only by CD4 T cells that recognize target alloantigen, processed and presented by the allospecific B cell. We demonstrate that in an alloresponse to multiple MHC disparities, cognate help for class-switched alloantibody may also be provided by CD4 T cells specific for a second "helper" alloantigen. This response was much shorter-lived than when help was provided conventionally, by Th cell recognition of target alloantigen. Nevertheless, long-lasting humoral alloimmunity developed when T cell memory against the helper alloantigen was first generated. Costimulatory blockade abrogated alloantibody produced through naive Th cell recognition of target alloantigen but, crucially, blockade was ineffective when help was provided by memory responses to the accessory helper alloantigen. These results suggest that memory Th cell responses against previously encountered graft alloantigen may be the dominant mechanism for providing help to generate new specificities of alloantibody in transplant patients receiving immunosuppression.
authors.affiliation: Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Conlon
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Cole
authors.forename: Reza
authors.initials: R
authors.lastname: Motallebzadeh
authors.forename: Inês
authors.initials: I
authors.lastname: Harper
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Callaghan
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.forename: Kourosh
authors.initials: K
authors.lastname: Saeb-Parsy
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D005260:Female; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory / Q000276:immunology*; D007518:Isoantibodies / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D007518:Isoantibodies