Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it.
Partial T cell depletion is used in solid organ transplantation as a valuable strategy of peritransplant induction immunosuppression. Using a murine cardiac allograft model, we recently demonstrated that this led to lymphopenia-induced (homeostatic) proliferation among the residual nondepleted lymphocytes. Rather than promoting tolerance, peritransplant T cell-depleting Abs actually resulted in resistance to tolerance induction by costimulatory blockade. In this study we show that memory T cells predominate shortly after subtotal lymphodepletion due to two distinct mechanisms: relative resistance to depletion and enhanced homeostatic proliferation. In contrast, regulatory cells (CD4+ CD25+ Foxp3+) are depleted as efficiently as nonregulatory cells and exhibit reduced homeostatic expansion compared with memory cells. The resistance to tolerance induction seen with subtotal T cell depletion can be overcome in two different ways: first, by the adoptive transfer of additional unprimed regulatory cells at the time of transplant, and second, by the adjunctive use of nondepleting anti-CD4 and anti-CD8 mAbs, which effectively block homeostatic expansion. We conclude that the resistance to tolerance induction seen after subtotal lymphocyte depletion can be attributed to alterations in the balance of naive, memory, and regulatory T cells. These data have clinically relevant implications related to the development of novel strategies to overcome resistance to tolerance.
Neujahr
David C
DC
Department of Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Chen
Chuangqi
C
Huang
Xiaolun
X
Markmann
James F
JF
Cobbold
Stephen
S
Waldmann
Herman
H
Sayegh
Mohamed H
MH
Hancock
Wayne W
WW
Turka
Laurence A
LA
D019264:Adoptive Transfer; D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D049109:Cell Proliferation; D016027:Heart Transplantation / Q000276:immunology; D006706:Homeostasis; D006801:Humans; D007156:Immunologic Memory; D008212:Lymphocyte Depletion / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D000961:Antilymphocyte Serum