Germinal center alloantibody responses are mediated exclusively by indirect-pathway CD4 T follicular helper cells.
The durable alloantibody responses that develop in organ transplant patients indicate long-lived plasma cell output from T-dependent germinal centers (GCs), but which of the two pathways of CD4 T cell allorecognition is responsible for generating allospecific T follicular helper cells remains unclear. This was addressed by reconstituting T cell-deficient mice with monoclonal populations of TCR-transgenic CD4 T cells that recognized alloantigen only as conformationally intact protein (direct pathway) or only as self-restricted allopeptide (indirect pathway) and then assessing the alloantibody response to a heart graft. Recipients reconstituted with indirect-pathway CD4 T cells developed long-lasting IgG alloantibody responses, with splenic GCs and allospecific bone marrow plasma cells readily detectable 50 d after heart transplantation. Differentiation of the transferred CD4 T cells into T follicular helper cells was confirmed by follicular localization and by acquisition of signature phenotype. In contrast, IgG alloantibody was not detectable in recipient mice reconstituted with direct-pathway CD4 T cells. Neither prolongation of the response by preventing NK cell killing of donor dendritic cells nor prior immunization to develop CD4 T cell memory altered the inability of the direct pathway to provide allospecific B cell help. CD4 T cell help for GC alloantibody responses is provided exclusively via the indirect-allorecognition pathway.
Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK.
Thomas M
TM
Conlon
Kourosh
K
Saeb-Parsy
Jennifer L
JL
Cole
Reza
R
Motallebzadeh
M Saeed
MS
Qureshi
Sylvia
S
Rehakova
Margaret C
MC
Negus
Chris J
CJ
Callaghan
Eleanor M
EM
Bolton
J Andrew
JA
Bradley
Gavin J
GJ
Pettigrew
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D014181:Transplantation Immunology / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D007518:Isoantibodies