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Lowest numbers of primary CD8+ T cells can reconstitute protective immunity upon adoptive immunotherapy

Christian Stemberger, Patricia Graef, Marcus Odendahl, Julia Albrecht, Georg Dössinger, Florian Anderl, Veit R. Buchholz, Georg Gasteiger, Matthias Schiemann, Götz U. Grigoleit, Friedhelm R. Schuster, Arndt Borkhardt, Birgitta Versluys, Torsten Tonn, Erhard Seifried, Hermann Einsele, Lothar Germeroth, Dirk H. Busch, Michael Neuenhahn

Key points

  • Lowest numbers of ex vivo selected CD8+ memory T cells can reconstitute pathogen-specific immunity in immuno-compromised hosts.

Abstract

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are threatened by potentially lethal viral manifestations like Cytomegalovirus (CMV) reactivation. Since the success of todays' virostatic treatment is limited by side effects and resistance development, adoptive transfer of virus-specific memory T cells derived from the stem cell donor has been proposed as an alternative therapeutic strategy. In this context, dose minimization of adoptively transferred T cells might be warranted for the avoidance of graft versus host disease (GvHD), in particular in prophylactic settings after T cell-depleting allo-HSCT protocols. To establish a lower limit for successful adoptive T cell therapy, we conducted low dose CD8+ T cell transfers in the well-established murine Listeria monocytogenes (L.m.) infection model. MHC-Streptamer-enriched antigen-specific CD62Lhi, but not CD62Llo CD8+ memory T cells proliferated, differentiated and protected against L.m. infections after prophylactic application. Even progenies derived from one single CD62Lhi L.m.-specific CD8+ T cell could be protective against bacterial challenge. In analogy, low dose transfers of Streptamer-enriched human CMV-specific CD8+ T cells into allo-HSCT recipients led to strong pathogen-specific T cell expansion in a compassionate-use setting. In summary, low dose adoptive T cell transfer could be a promising strategy particularly for prophylactic treatment of infectious complications after allo-HSCT.

  • Submitted December 31, 2013.
  • Accepted April 20, 2014.