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Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
TNF is a proinflammatory cytokine with opposing death/no-death
effects in vivo and in vitro. Our studies showed that TNF regulates
mouse thymocyte production, inducing both apoptosis and proliferation
of the most immature
CD3-CD4-CD8- triple negative
(TN) subset within a broad range of dosages
(101–105 pg/ml) in the presence of IL-7. TNF
apoptosis affected only the TN3 (CD44-CD25+)
and TN4 (CD44-CD25-) subsets that expressed
both TNFR-p55 and -p75. Although each TNFR alone could mediate TNF
apoptosis, maximal apoptosis was seen in C57BL/6J wild type, which
expressed both TNFRs. TNF also induced proliferation of TN3 cells at
higher doses (104–105 pg/ml) mediated only by
TNFR-p75. Both anti-TNFR-p55 and -TNFR-p75 mAb inhibited apoptosis
but only anti-p75 inhibited proliferation. TNF also regulated TN
proliferation to IL-7 because TNFR knockout (KO), TNF KO, and
TNF/lymphotoxin 
and 
triple KO mice showed 2- to 3-fold
increased responses not seen in C57BL/6J wild type. In vivo, TNFR KO
mice showed thymic hypertrophy with a 60% increase in total
thymocytes, with no effect on the CD4/CD8 subsets. We conclude that TNF
maintains homeostatic control of total thymocyte production by negative
selection of TN3 and TN4 prothymocytes and down-regulation of their
proliferation to endogenous IL-7.
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