Transplant conditions determine the contribution of homeostatically expanded donor CD8 memory cells to host lymphoid reconstitution following syngeneic HCT

Abstract

To investigate the ability of donor CD8 memory (CD8 TM) cells to expand in recipients following syngeneic hematopoietic stem cell transplants (HCT). The influence of clinically important transplant parameters--conditioning level, delayed infusion and dose--on the homeostatic expansion and overall contribution of donor CD8 TM to host CD8 reconstitution was determined. Lymphopenia-induced CD8 TM homeostatic expansion was examined in a syngeneic murine HCT model. Antigen specific CD8 TM included both T-cell receptor transgenic and nontransgenic populations. An ex vivo technique using antigen, interleukin (IL)-2, and IL-15 was used to generate homogenous transgenic CD8 TM (i.e., central memory) and was adapted to enrich the heterogeneous nontransgenic CD8 population specific for a nonameric epitope. Both transgenic and naturally occurring CD8 memory populations, derived in vivo or generated ex vivo, underwent a similar kinetic pattern of homeostatic expansion following transplantation into ablatively conditioned syngeneic recipients. Transplant parameters, i.e., lower conditioning, delayed infusion, and lower donor CD8 cell numbers shortened the period of expansion and lowered the steady-state numbers. The pattern of CD8 TM expansion was dependent on conditioning levels, time of infusion, and dose. Transplantation of varying donor CD8 TM numbers demonstrated there was a maximal donor cell contribution to host CD8 reconstitution. The application of multiple well-defined memory CD8 populations supports the notion that these findings are characteristic of memory CD8 cells in general.