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 an n-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.
This work was supported by doctoral studentships from the Alberta Diabetes Institute and Alberta Innovates Health Solutions (to K.K.E.) and a senior scholar award from Alberta Innovates Health Solutions (to C.C.A.).
Abbreviations used in this article:
- dendritic cell
- hematopoietic stem cell
- lymphopenia-induced proliferation
- peripherally generated Treg
- recent thymic emigrant
- secondary lymphoid organ
- conventional T cell
- regulatory T cell
- Received November 8, 2016.
- Accepted January 10, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.