Two Strikes and You're Out? The Pathogenic Interplay of Coinhibitor Deficiency and Lymphopenia-Induced Proliferation.
Lymphopenia-induced proliferation (LIP) occurs when resources for T cell survival in a host are in excess. LIP has been associated with the development of inflammatory disease in situations where an additional disease-predisposing cofactor is present during LIP. This has led to the view of LIP-driven autoimmunity as a two hit model; however, not all cofactors have equal ability to precipitate autoimmunity and we have recently shown that in some circumstances, such as the absence of the coinhibitory molecule PD-1, additional hits are required. Herein we review factors controlling LIP, including coinhibitory molecules and other attenuators of TCR signaling, with a focus on their contribution to LIP-driven autoimmunity. Rather than viewing LIP-associated autoimmunity as ann-hit model, we suggest a more quantitative view of lymphopenia with respect to the factors that promote LIP as a tool to predict autoimmune potential and to inform tumor immunotherapy approaches.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; colinand@ualberta.ca ellestad@ualberta.ca.|Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Kristofor K
0000-0001-9350-4977
KK
Ellestad
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; colinand@ualberta.ca ellestad@ualberta.ca.|Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; and.|Department of Surgery, University of Alberta, Edmonton, Alberta T6G 2B7, Canada.
Colin C
CC
Anderson
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D049109:Cell Proliferation / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*