Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

TY - JOUR

T1 - Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

AU - Wang, Xiuli

AU - Berger, Carolina

AU - Wong, ChingLam W

AU - Forman, Stephen J

AU - Riddell, Stanley R

AU - Jensen, Michael C

PY - 2011/2/10

Y1 - 2011/2/10

N2 - 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.

AB - 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.

KW - Adoptive Transfer

KW - Animals

KW - Antigens, Viral

KW - CD8-Positive T-Lymphocytes/cytology

KW - Cell Death/immunology

KW - Cell Differentiation/immunology

KW - Cell Proliferation

KW - Cytomegalovirus/immunology

KW - Humans

KW - Immunologic Memory

KW - Immunotherapy, Adoptive

KW - In Vitro Techniques

KW - Interleukin-15/biosynthesis

KW - L-Selectin/metabolism

KW - Leukocyte Common Antigens/metabolism

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Mice, Transgenic

KW - Models, Animal

KW - Phosphoproteins/immunology

KW - Transplantation, Heterologous

KW - Viral Matrix Proteins/immunology

U2 - 10.1182/blood-2010-10-310599

DO - 10.1182/blood-2010-10-310599

M3 - SCORING: Journal article

C2 - 21123821

VL - 117

SP - 1888

EP - 1898

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 6

ER -