Phenotype and homing of CD4 tumor-specific T cells is modulated by tumor bulk.
Technical difficulties in tracking endogenous CD4 T lymphocytes have limited the characterization of tumor-specific CD4 T cell responses. Using fluorescent MHC class II/peptide multimers, we defined the fate of endogenous Leishmania receptor for activated C kinase (LACK)-specific CD4 T cells in mice bearing LACK-expressing TS/A tumors. LACK-specific CD44(high)CD62L(low) CD4 T cells accumulated in the draining lymph nodes and had characteristics of effector cells, secreting IL-2 and IFN-gamma upon Ag restimulation. Increased frequencies of CD44(high)CD62L(low) LACK-experienced cells were also detected in the spleen, lung, liver, and tumor itself, but not in nondraining lymph nodes, where the cells maintained a naive phenotype. The absence of systemic redistribution of LACK-specific memory T cells correlated with the presence of tumor. Indeed, LACK-specific CD4 T cells with central memory features (IL-2(+)IFN-gamma(-)CD44(high)CD62L(high) cells) accumulated in all peripheral lymph nodes of mice immunized with LACK-pulsed dendritic cells and after tumor resection. Together, our data demonstrate that although tumor-specific CD4 effector T cells producing IFN-gamma are continuously generated in the presence of tumor, central memory CD4 T cells accumulate only after tumor resection. Thus, the continuous stimulation of tumor-specific CD4 T cells in tumor-bearing mice appears to hinder the systemic accumulation of central memory CD4 T lymphocytes.
Cancer Immunotherapy and Gene Therapy Program, S. Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy.
Fabio
F
Benigni
Valérie S
VS
Zimmermann
Stephanie
S
Hugues
Stefano
S
Caserta
Veronica
V
Basso
Laura
L
Rivino
Elizabeth
E
Ingulli
Laurent
L
Malherbe
Nicolas
N
Glaichenhaus
Anna
A
Mondino
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D000595:Amino Acid Sequence; D000818:Animals; D000953:Antigens, Protozoan / Q000096:biosynthesis / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000601:surgery; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D015800:Protozoan Proteins / Q000096:biosynthesis / Q000276:immunology
D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C111389:I-Ad antigen; D015800:Protozoan Proteins; C093139:LACK antigen, Leishmania; D007371:Interferon-gamma