The Central Role of CD4(+) T Cells in the Antitumor Immune Response

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 1998 Dec 22

PMID 9858522

Citations 422

Authors

K Hung

R Hayashi

C Lowenstein

D Pardoll

H Levitsky

Affiliations

Soon will be listed here.

Abstract

The induction of optimal systemic antitumor immunity involves the priming of both CD4(+) and CD8(+) T cells specific for tumor-associated antigens. The role of CD4(+) T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8(+) cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4(+) T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4(+) T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.

Citing Articles

Type 2 immunity in allergic diseases.

Ogulur I, Mitamura Y, Yazici D, Pat Y, Ardicli S, Li M Cell Mol Immunol. 2025; 22(3):211-242.

PMID: 39962262 PMC: 11868591. DOI: 10.1038/s41423-025-01261-2.

Impact of radiation dose to immune cells on survival in patients with esophageal cancer receiving neoadjuvant chemoradiotherapy: a retrospective analysis.

Zhao J, Wang K, Li Y, Hu X, Liu H, Zhao J BMC Cancer. 2025; 25(1):238.

PMID: 39934708 PMC: 11817987. DOI: 10.1186/s12885-025-13602-5.

CD4+ T helper 2 cell-macrophage crosstalk induces IL-24-mediated breast cancer suppression.

Wang B, Xia Y, Zhou C, Zeng Y, Son H, Demehri S JCI Insight. 2025; 10(1.

PMID: 39782693 PMC: 11721301. DOI: 10.1172/jci.insight.180962.

Reinventing type 2 immunity in cancer.

Wagner M, Nishikawa H, Koyasu S Nature. 2025; 637(8045):296-303.

PMID: 39780006 DOI: 10.1038/s41586-024-08194-2.

Impact of T cell characteristics on CAR-T cell therapy in hematological malignancies.

Tao Z, Chyra Z, Kotulova J, Celichowski P, Mihalyova J, Charvatova S Blood Cancer J. 2024; 14(1):213.

PMID: 39627220 PMC: 11615218. DOI: 10.1038/s41408-024-01193-6.

References

Stuehr D, Nathan C . Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989; 169(5):1543-55. PMC: 2189318. DOI: 10.1084/jem.169.5.1543. View

Belosevic M, Finbloom D, van der Meide P, Slayter M, Nacy C . Administration of monoclonal anti-IFN-gamma antibodies in vivo abrogates natural resistance of C3H/HeN mice to infection with Leishmania major. J Immunol. 1989; 143(1):266-74. View

Liew F, Millott S, Li Y, Lelchuk R, Chan W, Ziltener H . Macrophage activation by interferon-gamma from host-protective T cells is inhibited by interleukin (IL)3 and IL4 produced by disease-promoting T cells in leishmaniasis. Eur J Immunol. 1989; 19(7):1227-32. DOI: 10.1002/eji.1830190712. View

Fiorentino D, Bond M, Mosmann T . Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989; 170(6):2081-95. PMC: 2189521. DOI: 10.1084/jem.170.6.2081. View

Green S, Meltzer M, Hibbs Jr J, Nacy C . Activated macrophages destroy intracellular Leishmania major amastigotes by an L-arginine-dependent killing mechanism. J Immunol. 1990; 144(1):278-83. View

Sadick M, Heinzel F, Holaday B, Pu R, Dawkins R, Locksley R . Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990; 171(1):115-27. PMC: 2187647. DOI: 10.1084/jem.171.1.115. View

Street N, Schumacher J, Fong T, Bass H, Fiorentino D, Leverah J . Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990; 144(5):1629-39. View

Liew F, Millott S, Parkinson C, Palmer R, Moncada S . Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from L-arginine. J Immunol. 1990; 144(12):4794-7. View

Liew F, Li Y, Millott S . Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide. J Immunol. 1990; 145(12):4306-10. View

10.

Mauel J, Ransijn A . Killing of Leishmania parasites in activated murine macrophages is based on an L-arginine-dependent process that produces nitrogen derivatives. J Leukoc Biol. 1991; 49(1):73-82. DOI: 10.1002/jlb.49.1.73. View

11.

Pearce E, Caspar P, Grzych J, Lewis F, Sher A . Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. 1991; 173(1):159-66. PMC: 2118762. DOI: 10.1084/jem.173.1.159. View

12.

Liew F, Li Y, Millott S . Tumour necrosis factor (TNF-alpha) in leishmaniasis. II. TNF-alpha-induced macrophage leishmanicidal activity is mediated by nitric oxide from L-arginine. Immunology. 1990; 71(4):556-9. PMC: 1384878. View

13.

Schilham M, Rahemtulla A, Kundig T, Vollenweider M, Potter J, van Ewijk W . CD8 is needed for development of cytotoxic T cells but not helper T cells. Cell. 1991; 65(3):443-9. DOI: 10.1016/0092-8674(91)90462-8. View

14.

Oswald I, Wynn T, Sher A, James S . Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc Natl Acad Sci U S A. 1992; 89(18):8676-80. PMC: 49983. DOI: 10.1073/pnas.89.18.8676. View

15.

Gazzinelli R, Oswald I, Hieny S, James S, Sher A . The microbicidal activity of interferon-gamma-treated macrophages against Trypanosoma cruzi involves an L-arginine-dependent, nitrogen oxide-mediated mechanism inhibitable by interleukin-10 and transforming growth factor-beta. Eur J Immunol. 1992; 22(10):2501-6. DOI: 10.1002/eji.1830221006. View

16.

Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S . Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992; 176(6):1693-702. PMC: 2119469. DOI: 10.1084/jem.176.6.1693. View

17.

Dalton D, Keshav S, Figari I, Bradley A, Stewart T . Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993; 259(5102):1739-42. DOI: 10.1126/science.8456300. View

18.

Kopf M, Le Gros G, Bachmann M, Lamers M, Bluethmann H, Kohler G . Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993; 362(6417):245-8. DOI: 10.1038/362245a0. View

19.

Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K . Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci U S A. 1993; 90(8):3539-43. PMC: 46336. DOI: 10.1073/pnas.90.8.3539. View

20.

Costa J, Matossian K, Resnick M, Beil W, Wong D, Gordon J . Human eosinophils can express the cytokines tumor necrosis factor-alpha and macrophage inflammatory protein-1 alpha. J Clin Invest. 1993; 91(6):2673-84. PMC: 443331. DOI: 10.1172/JCI116506. View