Impaired negative regulation of homeostatically proliferating T cells.
Acute lymphopenia-induced homeostatic proliferation (HP) of T cells promotes antitumor 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-beta. 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-beta1-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.
Shvets
Anna
A
Department of Laboratory Medicine, St Michael's Hospital and University of Toronto, Toronto, ON.
Chakrabarti
Rabindranath
R
Gonzalez-Quintial
Rosana
R
Baccala
Roberto
R
Theofilopoulos
Argyrios N
AN
Prud'homme
Gérald J
GJ
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006706:Homeostasis / Q000276:immunology*; D008231:Lymphopenia / Q000276:immunology*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1
D015703:Antigens, CD; D000943:Antigens, Differentiation; D001324:Autoantigens; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016212:Transforming Growth Factor beta; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475824:Vtcn1 protein, mouse