title: Homeostatic proliferation is a barrier to transplantation tolerance.
abstract: Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells. Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials. But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation, may induce acquisition of functional memory T cells. Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Philadelphia 19104, USA.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Wu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.forename: Chuangqi
authors.initials: C
authors.lastname: Chen
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Xiaolun
authors.initials: X
authors.lastname: Huang
authors.forename: James F
authors.initials: JF
authors.lastname: Markmann
authors.forename: Alireza
authors.initials: A
authors.lastname: Kassaee
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosengard
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D000818:Animals; D006706:Homeostasis; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D051379:Mice; D013045:Species Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014181:Transplantation Immunology