Submitted March 5, 2008
Accepted November 17, 2008
Impaired negative regulation of homeostatically proliferating T cells
Anna Shvets, Rabindranath Chakrabarti*, Rosana Gonzalez-Quintial, Roberto Baccala, Argyrios N Theofilopoulos, and Gerald J Prud'homme
Department of Laboratory Medicine, St. Michael's Hospital and University of Toronto, Toronto, ON, Canada
Department of Immunology, The Scripps Research Institute, La Jolla, CA, United States
* Corresponding author; email: chakrabartir{at}smh.toronto.on.ca.
Acute lymphopenia-induced homeostastic proliferation (HP) of T cells promotes anti-tumor immunity, but the mechanism is unclear. We hypothesized that this is due to a lack of inhibitory signals that allows activation of T cells with low affinity for self-antigens. Tumors resist immunity in part by expressing inhibitory molecules such as PD-1 ligand 1 (PD-L1), B7-H4 and TGF-
. In irradiated mice undergoing HP, we found that T cells displayed a severe deficit in the activation-induced expression of inhibitory molecules PD-1 and CTLA-4, and TGF-1-induced expression of Foxp3. HP T cells were also less suppressed by B7-H4/Ig and, unlike control T cells, failed to produce IL-10 in response to this molecule. This deficiency in regulation was reversed as normal T cell numbers were restored. We conclude that T cells are weakly regulated by inhibitory molecules during the acute phase of HP, which could explain their increased effectiveness in cancer immunotherapy.
