Dendritic cells internalise and re-present conformationally intact soluble MHC class I alloantigen for generation of alloantibody.
Following organ transplantation soluble MHC class I is released from the graft and may contribute to alloimmunity. We determined in a well-established rat model whether DC are able to internalise soluble MHC class I alloantigen and then re-present intact alloantigen to B cells and T cells for generation of an alloantibody or CD8 T cell response. PVG.RT1(u) BM-derived DC internalised (via an active process) and retained intact a recombinant soluble form of RT1-A(a) (sRT1-A(a)). When PVG.RT1(u) rats were immunised with sRT1-A(a)-pulsed syngeneic DC, they developed a strong anti-sRT1-A(a) alloantibody response and showed accelerated rejection of RT1-A(a)-disparate PVG.R8 heart grafts. Alloantibody production and accelerated heart graft rejection were both dependent on immunisation with viable sRT1-A(a)-pulsed DC. The alloantibody response to sRT1-A(a)-pulsed DC was directed exclusively against conformational epitopes expressed by sRT1-A(a) and not epitopes expressed, for example, by non-conformational sRT1-A(a) heavy chain. Immunisation with sRT1-A(a)-pulsed syngeneic DC did not stimulate a CD8 T cell response. Our findings suggest a novel alloantigen recognition pathway whereby soluble MHC class I alloantigen released from an allograft may be taken up by recipient DC and presented in an intact unprocessed form to B cells for the generation of an alloantibody response.
Curry
Allison J
AJ
Department of Surgery, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
Pettigrew
Gavin J
GJ
Negus
Margaret C
MC
Easterfield
Alistair J
AJ
Young
Joyce L
JL
Bolton
Eleanor M
EM
Bradley
J Andrew
JA
D000818:Animals; D020296:Animals, Congenic; D017951:Antigen Presentation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism*; D007518:Isoantibodies / Q000096:biosynthesis*; D011487:Protein Conformation; D051381:Rats
D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies; C038353:histocompatibility antigens RT, rat