Identification of a coordinated CD8 and CD4 T cell response directed against mismatched HLA Class I causing severe acute graft-versus-host disease.
After HLA class I-mismatched stem cell transplantation, allo-HLA-directed CD8 T cell responses can be activated without the help of CD4 T cells if memory CD8 T cells cross-reactive against the allo-HLA class I are present or if naïve CD8 T cells are administered during inflammatory conditions. However, in the absence of inflammatory conditions, cooperation between CD4 and CD8 T cells likely is required for an effective primary CD8 T cell response directed against allo-HLA class I. In this study we investigated whether a coordinated response of CD8 and CD4 T cells could be demonstrated in an HLA class I-directed immune response in a patient who developed severe graft-versus-host disease (GVHD) after the administration HLA-A2-mismatched donor lymphocyte infusion in the absence of inflammatory conditions. A previously administered donor lymphocyte infusion from the same donor did not lead to an immune response, excluding the presence of a substantial pool of CD8 T cells cross-reactive against HLA-A2 within the memory T cell compartment of the donor. Analysis of isolated donor CD8 and CD4 T cell clones activated during the GVHD revealed a polyclonal CD8 T cell response directed against the mismatched HLA-A2 and a polyclonal CD4 T cell response recognizing HLA-A2-derived peptides presented in HLA class II. In addition, leukemic blasts present at the time of the emergence of GVHD expressed HLA-A2 and HLA class II and could activate both the CD4 and CD8 alloreactive T cells. Our results demonstrate that the GVHD was mediated by a cooperative CD4 and CD8 response directed against the mismatched HLA-A2 and suggest that leukemic blasts possibly activated this CD8 and CD4 T cell response.
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
Avital L
AL
Amir
Renate S
RS
Hagedoorn
Simone A P
SA
van Luxemburg-Heijs
Erik W A
EW
Marijt
Alwine B
AB
Kruisselbrink
J H
JH
Frederik Falkenburg
Mirjam H M
MH
Heemskerk
D000208:Acute Disease; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D015789:HLA-A2 Antigen / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007156:Immunologic Memory; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation
D015789:HLA-A2 Antigen; D000949:Histocompatibility Antigens Class II