Antigen-specific CD4 T-Cell Help Is Required to Activate a Memory CD8 T Cell

to a Fully Functional Tumor Killer Cell

高丰光

Background

CD8 mCTLs3 play a major role in the elimination of viruses and tumors

Before mCTLs can eliminate viruses and tumors, these cells are required to roliferate and acquire effector function.

The role CD4 T-helper cells play in the induction of CD8 effector T cells from naive precursors is known

the role of T-helper cells in the activation of mCTLs when the antigen is presented by the tumor is not established.

Question

How about T-helper cells in the activation of memory T cells?

相关说明 OT-1 mice : 表达 SIINFEKL 特异性 TCR OVA ：鸡卵白蛋白 OVA CTL epitope: SIINFEKL OVA Th epitope:ISQAVHAAHAEI-NEAGROVA

（ OVT ）

RAG-1 KO mice: C57BL/6 mice: IFA/CFA/KLH EG7 cell line EL4 cell line

相关步骤 mCTL and eCTL generation specific Th generation mCTL transfer tumor challenge

OT-1 mice 的基本特征

mCTL generation

mCTL generation

mCTL generation

CTL+Th

CTL+KLH

CTL

Th

KLH

Control0.0

0.2

0.4

0.6

0.8

1.0

CTL+ThCTL+KLHCTLThKLHControl

Tu

mo

ur

wei

gh

t (g

)

CD8+ Memory T Cells Need Antigen-specific CD4+T-helper Cells to Achieve Tumor Protection

Absence of tumor protection in mice without antigen-specific T-helper cells is not because of lower levels of tumor antigen

(SIINFEKL)-specific CD8+ T cells.

In contrast to mCTLs, eCTLs do not need T help to kill tumor

Study of the long-lived memory CD8+ T cells generated in C57BL/6J mice

1.Rowe HM, Lopes L, Ikeda Y, et al.Immunization with a lentiviral vector stimulates both CD4 and CD8 T cell responses to an ovalbumin transgene MOLECULAR THERAPY 13 (2): 310-319 FEB 2006 Times Cited: 0 2. Thompson JA, Dissanayake SK, Ksander BR, et al.Tumor cells transduced with the MHC class II transactivator and CD80 activate tumor-specific CD4(+) T cells whether or not they are silenced for invariant chain CANCER RESEARCH 66 (2): 1147-1154 JAN 15 2006 Times Cited: 0 3. Salucci V, Mennuni C, Calvaruso F, et al.CD8(+) T-cell tolerance can be broken by an adenoviral vaccine while CD4(+) T-cell tolerance is broken by additional co-administration of a Toll-like receptor ligand SCANDINAVIAN JOURNAL OF IMMUNOLOGY 63 (1): 35-41 JAN 2006 Times Cited: 0 4. Radford KJ, Vari F, Hart DNJVaccine strategies to treat lymphoproliferative disorders PATHOLOGY 37 (6): 534-550 DEC 2005 Times Cited: 1 5. Hu DE, Kettunen MI, Brindle KMMonitoring T-lymphocyte trafficking in tumors undergoing immune rejection MAGNETIC RESONANCE IN MEDICINE 54 (6): 1473-1479 DEC 2005 Times Cited: 0 6. Van Meirvenne S, Dullaers M, Heirman C, et al.In vivo depletion of CD4(+)CD25(+) regulatory T cells enhances the antigen-specific primary and memory CTL response elicited by mature mRNA-electroporated dendritic cells MOLECULAR THERAPY 12 (5): 922-932 NOV 2005 Times Cited: 2 7. Miyazaki M, Nakatsura T, Yokomine K, et al.DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4(+) T cells and CD8(+) T cells CANCER SCIENCE 96 (10): 695-705 OCT 2005 Times Cited: 1 8.Kumaraguru U, Banerjee K, Rouse BTIn vivo rescue of defective memory CD8(+) T cells by cognate helper T cells JOURNAL OF LEUKOCYTE BIOLOGY 78 (4): 879-887 OCT 2005 Times Cited: 0

9. Ostrand-Rosenberg SCD4(+) T lymphocytes: A critical component of antitumor immunity CANCER INVESTIGATION 23 (5): 413-419 2005 Times Cited: 2 10. Knutson KL, Disis MLTumor antigen-specific T helper cells in cancer immunity and immunotherapy CANCER IMMUNOLOGY IMMUNOTHERAPY 54 (8): 721-728 AUG 2005 Times Cited: 4

11.Kutzler MA, Robinson TM, Chattergoon MA, et al.Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T cells that are partially independent of CD4 T cell help JOURNAL OF IMMUNOLOGY 175 (1): 112-123 JUL 1 2005 Times Cited: 2 12. Meyer-Wentrup F, Richter G, Burdach SIdentification of an immunogenic EWS-FLI1-derived HLA-DR-restricted T helper cell epitope PEDIATRIC HEMATOLOGY AND ONCOLOGY 22 (4): 297-308 JUN 2005 Times Cited: 0 13. Timar J, Ladanyi A, Forster-Horvath C, et al.Neoadjuvant immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and tumor microenvironment: A multicenter phase II clinical trial JOURNAL OF CLINICAL ONCOLOGY 23 (15): 3421-3432 MAY 20 2005 Times Cited: 1 14. Tscharke DC, Suhrbier AFrom mice to humans murine intelligence for human CD8(+) T cell vaccine design EXPERT OPINION ON BIOLOGICAL THERAPY 5 (2): 263-271 FEB 2005 Times Cited: 1 15.Villada IB, Barracco MM, Ziol M, et al.Spontaneous regression of grade 3 vulvar intraepithelial neoplasia associated with human papillomavirus-16-specific CD4(+) and CD8(+) T-cell responses CANCER RESEARCH 64 (23): 8761-8766 DEC 1 2004 Times Cited: 3 16. Altin JG, van Broekhoven CL, Parish CRTargeting dendritic cells with antigen-containing liposomes: antitumour immunity EXPERT OPINION ON BIOLOGICAL THERAPY 4 (11): 1735-1747 NOV 2004 Times Cited: 1 17. Leggatt GR, Narayan S, Fernando GJP, et al.Changes to peptide structure, not concentration, contribute to expansion of the lowest avidity cytotoxic T lymphocytes JOURNAL OF LEUKOCYTE BIOLOGY 76 (4): 787-795 OCT 2004 Times Cited: 0

18. Hsueh EC, Farnatiga E, Shu S, et al.Peripheral blood CD4+ T-cell response before postoperative active immunotherapy correlates with clinical outcome in metastatic melanoma ANNALS OF SURGICAL ONCOLOGY 11 (10): 892-899 OCT 2004 Times Cited: 0 19. Hiraoka K, Yamamoto S, Otsuru S, et al.Enhanced tumor-specific long-term immunity of hemaggluttinating virus of Japan-mediated dendritic cell-tumor fused cell vaccination-by coadministration with CpG oligodeoxynucleotides JOURNAL OF IMMUNOLOGY 173 (7): 4297-4307 OCT 1 2004 Times Cited: 1 20. Chiang EY, Stroynowski IA nonclassical MHC class I molecule restricts CTL-mediated rejection of a syngeneic melanoma tumor JOURNAL OF IMMUNOLOGY 173 (7): 4394-4401 OCT 1 2004 Times Cited: 3

21. Wong R, Lau R, Chang J, et al.Immune responses to a class II helper peptide epitope in patients with stage III/IV resected melanoma CLINICAL CANCER RESEARCH 10 (15): 5004-5013 AUG 1 2004 Times Cited: 6 22. Sun JB, Eriksson K, Li BL, et al.Vaccination with dendritic cells pulsed in vitro with tumor antigen conjugated to cholera toxin efficiently induces specific turnoricidal CD8(+) cytotoxic lymphocytes dependent on cyclic AMP activation of dendritic cells CLINICAL IMMUNOLOGY 112 (1): 35-44 JUL 2004 Times Cited: 3 23. Zoller MImmunotherapy of cancer for the elderly patient: does allogeneic bone marrow transplantation after nonmyeloablative conditioning provide a new option? CANCER IMMUNOLOGY IMMUNOTHERAPY 53 (8): 659-676 AUG 2004 Times Cited: 1 24. Chen QY, Jackson H, Parente P, et al.Immunodominant CD4(+) responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 101 (25): 9363-9368 JUN 22 2004 Times Cited: 12 25. Nicholl M, Lodge A, Brown I, et al.Restored immune response to an MHC-II-restricted antigen in tumor-bearing hosts after elimination of regulatory T cells JOURNAL OF PEDIATRIC SURGERY 39 (6): 941-946 JUN 2004 Times Cited: 3

26. Shen L, Schroers R, Hammer J, et al.Identification of a MHC class-II restricted epitope in carcinoembryonic antigen CANCER IMMUNOLOGY IMMUNOTHERAPY 53 (5): 391-403 MAY 2004 Times Cited: 4 27.Ruiz M, Kobayashi H, Lasarte JJ, et al.Identification and characterization of a T-helper peptide from carcinoembryonic antigen CLINICAL CANCER RESEARCH 10 (8): 2860-2867 APR 15 2004 Times Cited: 2 28.Slager EH, van der Minne CE, Kruse M, et al.Identification of multiple HLA-DR-restricted epitopes of the tumor-associated antigen CAMEL by CD4(+) Th1/Th2 lymphocytes JOURNAL OF IMMUNOLOGY 172 (8): 5095-5102 APR 15 2004 Times Cited: 3 29. Johansen P, Stamou P, Tascon RE, et al.CD4 T cells guarantee optimal competitive fitness of CD8 memory T cells EUROPEAN JOURNAL OF IMMUNOLOGY 34 (1): 91-97 JAN 2004 Times Cited: 7 30. Frazer IHPrevention of cervical cancer through papillomavirus vaccination NATURE REVIEWS IMMUNOLOGY 4 (1): 46-54 JAN 2004 Times Cited: 37

31. Liu XS, Xu Y, Hardy L, et al.IL-10 mediates suppression of the CD8 T cell IFN-gamma response to a novel viral epitope in a primed host JOURNAL OF IMMUNOLOGY 171 (9): 4765-4772 NOV 1 2003 Times Cited: 6 32. Nagorsen D, Scheibenbogen C, Marincola FM, et al.Natural T cell immunity against cancer CLINICAL CANCER RESEARCH 9 (12): 4296-4303 OCT 1 2003 Times Cited: 27 33. Tuyaerts S, Michiels A, Corthals J, et al.Induction of Influenza Matrix Protein 1 and MelanA-specific T lymphocytes in vitro using mRNA-electroporated dendritic cells CANCER GENE THERAPY 10 (9): 696-706 SEP 2003 Times Cited: 10 34.Finn OJCancer vaccines: Between the idea and the reality NATURE REVIEWS IMMUNOLOGY 3 (8): 630-641 AUG 2003 Times Cited: 108