Pathways of helper CD4 T cell allorecognition in generating alloantibody and CD8 T cell alloimmunity.
BACKGROUND
The relative contributions of the "direct" and "indirect" pathways of CD4 T cell allorecognition in providing help for generating effective humoral and CD8 T cell alloimmunity remain unclear. Here, the generation of alloantibody and cytotoxic CD8 T cell responses to a vascularized allograft were examined in a murine adoptive-transfer model in which help could only be provided by transferred CD4 T cells recognizing alloantigen exclusively through the direct pathway.


METHODS
Rejection kinetics and the development of alloantibody and cytotoxic CD8 T cell responses to MHC-mismatched H-2d heart grafts were compared when CD4 T cell help was present (wild-type H-2d recipients), or absent (CD4 T cell deficient, MHC class II-/- H-2b recipients [B6CII-/-]), or available only through the direct pathway (B6CII-/- mice reconstituted with wild-type CD4 T cells).


RESULTS
BALB/c allografts were rejected by B6 mice rapidly (median survival time [MST] 7 days) with strong CD8 T cell effector and alloantibody responses, but were rejected by B6CII-/- mice more slowly (MST 23 days), with markedly reduced CD8 T cell responses and no detectable alloantibody. CD4 T cell reconstitution of B6CII-/- recipients accelerated heart graft rejection to near that of wild-type recipients (MST 13 days), with complete restoration of cytotoxic CD8 T cell responses but without detectable IgM or IgG alloantibody.


CONCLUSIONS
Different pathways of helper T cell allorecognition are responsible for generating humoral and CD8 T cell alloimmunity. CD4 T cell help provided exclusively through the direct pathway generates strong cytotoxic CD8 T cell responses that effect rapid heart graft rejection.
Taylor
Anna L
AL
Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom.
Negus
Susanne L
SL
Negus
Margaret
M
Bolton
Eleanor M
EM
Bradley
J Andrew
JA
Pettigrew
Gavin J
GJ
D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies; D007371:Interferon-gamma