Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice.
In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (T(E)) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8(+) T(E) cells derived from purified CD45RO(+)CD62L(+) central memory (T(CM)) or CD45RO(+)CD62L(-) effector memory (T(EM)) precursors in an immunodeficient mouse model. The engraftment of T(CM)-derived effector cells (T(CM/E)) was dependent on human interleukin-15, and superior in magnitude and duration to T(EM)-derived effector cells (T(EM/E)). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8(+) T(CM/E) engraftment was polyclonal, suggesting that the ability to engraft is a general feature of T(CM/E.) CD8(+) T(EM/E) proliferated extensively after transfer but underwent rapid apoptosis. In contrast, T(CM/E) were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8(+) effector T cells derived from T(CM) precursors may be preferred for adoptive therapy based on superior engraftment fitness.
Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
Xiuli
X
Wang
Carolina
C
Berger
ChingLam W
CW
Wong
Stephen J
SJ
Forman
Stanley R
SR
Riddell
Michael C
MC
Jensen
D019264:Adoptive Transfer; D000818:Animals; D000956:Antigens, Viral; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D003587:Cytomegalovirus / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics; D019041:L-Selectin / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D023421:Models, Animal; D010750:Phosphoproteins / Q000276:immunology; D014183:Transplantation, Heterologous; D014763:Viral Matrix Proteins / Q000276:immunology
D000956:Antigens, Viral; D019409:Interleukin-15; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D019041:L-Selectin; D017493:Leukocyte Common Antigens