Naïve CD8 T cell activation by liver bone marrow-derived cells leads to a "neglected" IL-2low Bimhigh phenotype, poor CTL function and cell death.
OBJECTIVE
The occurrence of primary CD8 T cell activation within the liver, unique among the non-lymphoid organs, is now well accepted. However, the outcome of intrahepatic T cell activation remains controversial. We have previously reported that activation initiated by hepatocytes results in a tolerogenic phenotype characterized by low expression of CD25 and IL-2, poor cytotoxic T lymphocyte (CTL) function, and excessive expression of the pro-apoptotic protein Bim.


METHODS
To investigate whether this phenotype was due to activation in the absence of co-stimulation, we generated bone marrow (bm) radiation chimeras in which adoptively transferred naïve transgenic CD8 T cells were activated in the presence of co-stimulation by liver bm-derived cells.


RESULTS
Despite expressing pro-inflammatory cytokines, high levels of CD25 and CD54, donor T cells activated by liver bm-derived cells did not produce detectable IL-2 and displayed poor CTL function, suggesting incomplete acquisition of effector function. Simultaneously, these cells expressed high levels of Bim and died by neglect. Transfer of Bim-deficient T cells resulted in increased T cell numbers.


CONCLUSIONS
These results imply that expression of CD25 and CD54 is co-stimulation dependent and distinguishes T cell activated by hepatocytes and liver bm-derived cells. In contrast, low expression of IL-2, poor CTL function and excess Bim production represent a more universal phenotype defining T cells undergoing primary activation by both types of hepatic antigen presenting cells (APC). These results have important implications for transplantation, in which all liver antigen presenting cells contribute to activation of T cells specific for the allograft.
AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW 2050, Australia.
Lauren E
LE
Holz
Volker
V
Benseler
Michelle
M
Vo
Claire
C
McGuffog
Nico
N
Van Rooijen
Geoffrey W
GW
McCaughan
David G
DG
Bowen
Patrick
P
Bertolino
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D022781:Hepatocytes / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism*; D008099:Liver / Q000166:cytology* / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011828:Radiation Chimera
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D007376:Interleukin-2; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins