CD4+ T cells initiate pancreatic islet xenograft rejection via an interferon-gamma-dependent recruitment of macrophages and natural killer cells.
BACKGROUND
In this study, the mechanisms by which CD4+ T cells interact with the innate immune system in xenograft rejection were investigated.


METHODS
Fetal pig pancreas (FPP) grafts were transplanted into female SCID mice. The FPP recipient SCID mice were reconstituted with exogenous leukocytes obtained from male BALB/c mice.


RESULTS
Although nonreconstituted SCID recipients or recipients reconstituted with CD4+ T cell-depleted leukocytes showed indefinite FPP graft survival with very few macrophages infiltrating their grafts, reconstitution of SCID recipients with as few as 2x10(5) CD4+ T cells was sufficient to induce rapid xenograft rejection. CD4+ T cells secreted interferon-gamma but not interleukin-4 and initiated the activation and accumulation of macrophages and natural killer cells, that were responsible for the rapid graft destruction. Suppression of interferon-gamma prolonged graft survival and suppressed the macrophages and natural killer cell accumulation and activation.


CONCLUSIONS
These results demonstrate that CD4+ T cell-dependent cellular xenograft rejection was a result of macrophage and natural killer cell accumulation and activation, but was not mediated by eosinophils. Consistent with this was the finding that interferon-gamma but not interleukin-4 was in part responsible for mediating this effect.
Yi
Shounan
S
National Pancreas Transplant Unit, Westmead Hospital, Westmead, New South Wales 2145, Australia.
Feng
Ximin
X
Hawthorne
Wayne J
WJ
Patel
Anita T
AT
Walters
Stacey N
SN
O'Connell
Philip J
PJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D016332:Fetal Tissue Transplantation; D006084:Graft Rejection / Q000209:etiology*; D007371:Interferon-gamma / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma