The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells

Ronjon Chakraverty, Barry Flutter, Farnaz Fallah-Arani, Hyeon Seok Eom, Terry Means, Giovanna Andreola, Sebastian Schwarte, Jennifer Buchli, Pete Cotter, Guiling Zhao, Megan Sykes

Research output: Contribution to journalArticle

Abstract

We have examined how the host environment influences the graft-vs-leukemia (GVL) response following transfer of donor T cells to allogeneic chimeras. Donor T cells induce significant GVL when administered in large numbers to established mixed chimeras (MC). However, when using limiting numbers of T cells, we found that late transfer to MC induced less GVL than did early transfer to freshly irradiated allogeneic recipients. Late donor T cell transfer to MC was associated with marked accumulation of anti-host CD8 cells within the spleen, but delayed kinetics of differentiation, reduced expression of effector molecules including IFN-γ, impaired cytotoxicity, and higher rates of sustained apoptosis. Furthermore, in contrast to the spleen, we observed a significant delay in donor CD8 cell recruitment to the bone marrow, a key location for hematopoietic tumors. Increasing the numbers of T cells transferred to MC led to the enhancement of CTL activity and detectable increases in absolute numbers of IFN-γ+ cells without inducing graft-vs-host disease (GVHD). TLR-induced systemic inflammation accelerated differentiation of functional CTL in MC but was associated with severe GVHD. In the absence of inflammation, both recipient T and non-T cell populations impeded the full development of GVHD-inducing effector function. We conclude that per-cell deficits in the function of donor CD8 cells activated in MC may be overcome by transferring larger numbers of T cells without inducing GVHD.

Original languageEnglish
Pages (from-to)6820-6828
Number of pages9
JournalJournal of Immunology
Volume181
Issue number10
Publication statusPublished - Nov 15 2008

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

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    Chakraverty, R., Flutter, B., Fallah-Arani, F., Eom, H. S., Means, T., Andreola, G., Schwarte, S., Buchli, J., Cotter, P., Zhao, G., & Sykes, M. (2008). The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells. Journal of Immunology, 181(10), 6820-6828.