The host environment regulates the function of CD8+ graft-versus-host-reactive effector cells.
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-gamma, 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-gamma(+) 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.
Chakraverty
Ronjon
R
Transplantation Immunology Group, Department of Hematology, University College London, London, UK.
Flutter
Barry
B
Fallah-Arani
Farnaz
F
Eom
Hyeon-Seok
HS
Means
Terry
T
Andreola
Giovanna
G
Schwarte
Sebastian
S
Buchli
Jennifer
J
Cotter
Pete
P
Zhao
Guiling
G
Sykes
Megan
M
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000637:transplantation; D018183:Transplantation Chimera / Q000276:immunology