Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow.
We have investigated the mechanism of tolerance in a patient with severe combined immunodeficiency (SCID) transplanted with HLA-haploidentical, T cell-depleted bone marrow cells obtained from the mother. At 4 years after transplantation, T cells, natural killer (NK) cells, and a small percentage (2%) of B cells were found to be of donor origin, whereas monocytes and the majority of B cells remained of host origin. In primary mixed lymphocyte cultures (MLC), the engrafted T cells of the donor did not proliferate in response to the host cells, whereas untransplanted donor T cells showed good proliferative responses. However, CD4+ and CD8+ T-cell clones of donor origin with specificity for class II and class I HLA determinants of the host were isolated. CD8+, host-reactive T-cell clones displayed normal cytotoxic activity after stimulation with the host cells, but proliferative responses of CD4+, host-reactive T-cell clones were considerably reduced. In addition, both CD8+ and CD4+, host-reactive T-cell clones produced very low to undetectable levels of interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3 zeta subunit of the T-cell receptor (TcR) was normal, and after stimulation via CD3, Raf-1 and p42 mitogen activated protein (MAP) kinase were phosphorylated, indicating that this part of the signaling pathway after triggering of the TcR/CD3 complex is present. These results, together with our previous observation that dysfunctional, host-reactive T-cell clones can be isolated in SCID patients transplanted with fetal liver stem cells, demonstrate that lack of clonal deletion of host-reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.
Bacchetta
R
R
Human Immunology Department, DNAX Research Institute, Palo Alto, CA 94304-1104, USA.
Parkman
R
R
McMahon
M
M
Weinberg
K
K
Bigler
M
M
de Vries
J E
JE
Roncarolo
M G
MG
D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D002678:Chimera / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics; D006239:Haplotypes / Q000235:genetics / Q000276:immunology; D006648:Histocompatibility; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*
D016207:Cytokines; D006680:HLA Antigens; D007376:Interleukin-2; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor