Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow

R. Bacchetta, R. Parkman, M. McMahon, K. Weinberg, M. Bigler, J. E. De Vries, M. G. Roncarolo

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Abstract

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- γ, and granulocyte-macrophage colony-stimulating factor after specific antigenic activation, which may be responsible for their nonresponsive state in vivo. Expression of the CD3ζ 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 fatal liver stem cells, demonstrate that lack of clonal deletion of host- reactive T cells is a general phenomenon after HLA-mismatched stem cell transplantation.

Original languageEnglish
Pages (from-to)1944-1953
Number of pages10
JournalBlood
Volume85
Issue number7
Publication statusPublished - 1995

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ASJC Scopus subject areas

  • Hematology

Cite this

Bacchetta, R., Parkman, R., McMahon, M., Weinberg, K., Bigler, M., De Vries, J. E., & Roncarolo, M. G. (1995). Dysfunctional cytokine production by host-reactive T-cell clones isolated from a chimeric severe combined immunodeficiency patient transplanted with haploidentical bone marrow. Blood, 85(7), 1944-1953.