Journal Article
. 2013 Apr; 210(4):743-55.
doi: 10.1084/jem.20121190.

Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin

Michael A Curran 1 Theresa L Geiger  Welby Montalvo  Myoungjoo Kim  Steven L Reiner  Aymen Al-Shamkhani  Joseph C Sun  James P Allison  
  • PMID: 23547098
  •     48 References
  •     75 citations


4-1BB agonist antibody treatment induces a population of KLRG1(+) T cells that infiltrate melanoma tumors. We investigated the origin and function of these cells, as well as their place within established T cell paradigms. We find that these T cells, particularly the CD4 lineage, represent a novel phenotype characterized by enhanced, multipotent cytotoxicity. Distinct from described polarities, this T cell phenotype is driven by the T-box transcription factor Eomesodermin. Formation of this phenotype requires 4-1BB signaling on both T and antigen-presenting cells and the resulting production of the cytokines IL-27, IL-15, and IL-10. Furthermore, we find CD4(+) T cells bearing the signature features of this phenotype in the livers of mice infected with both bacterial and viral intracellular pathogens, suggesting a role for these cells in infectious immunity. These T cells constitute a novel phenotype that resolves multiple questions associated with 4-1BB activation, including how 4-1BB enhances tumor-specific cytotoxicity and how 4-1BB can promote tumor immunity while repressing autoimmunity.

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Nat Med, 2019 Jul 25; 25(8). PMID: 31332390    Free PMC article.
Highly Cited.
Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.
Todd Bartkowiak, Ashvin R Jaiswal, +8 authors, Michael A Curran.
Clin Cancer Res, 2018 Jan 06; 24(5). PMID: 29301830    Free PMC article.
Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology.
Paul David, Malgorzata Drabczyk-Pluta, +24 authors, Gennadiy Zelinskyy.
PLoS Pathog, 2020 Apr 01; 16(3). PMID: 32226027    Free PMC article.
Decoding the Role of Interleukin-30 in the Crosstalk Between Cancer and Myeloid Cells.
Emma Di Carlo.
Cells, 2020 Mar 08; 9(3). PMID: 32143355    Free PMC article.
4-1BB Agonism Combined With PD-L1 Blockade Increases the Number of Tissue-Resident CD8+ T Cells and Facilitates Tumor Abrogation.
Qiu-Xia Qu, Xin-Yun Zhu, +4 authors, Cheng Chen.
Front Immunol, 2020 May 12; 11. PMID: 32391001    Free PMC article.
The promise of combining cancer vaccine and checkpoint blockade for treating HPV-related cancer.
Takeo Shibata, Benjamin J Lieblong, Toshiyuki Sasagawa, Mayumi Nakagawa.
Cancer Treat Rev, 2019 Jul 16; 78. PMID: 31302573    Free PMC article.
Therapeutic Vaccines for HPV-Associated Malignancies.
Claire Smalley Rumfield, Nicholas Roller, +2 authors, Caroline Jochems.
Immunotargets Ther, 2020 Oct 30; 9. PMID: 33117742    Free PMC article.
Bone Morphogenic Proteins Are Immunoregulatory Cytokines Controlling FOXP3+ Treg Cells.
Lauren M Browning, Caroline Miller, +6 authors, Piotr Kraj.
Cell Rep, 2020 Oct 08; 33(1). PMID: 33027660    Free PMC article.
Co-inhibitory T cell receptor KLRG1: human cancer expression and efficacy of neutralization in murine cancer models.
Steven A Greenberg, Sek Won Kong, Evan Thompson, Stefano V Gulla.
Oncotarget, 2019 Mar 13; 10(14). PMID: 30858925    Free PMC article.
Is AAV-delivered IL-27 a potential immunotherapeutic for cancer?
Jin-Qing Liu, Jianmin Zhu, +6 authors, Xue-Feng Bai.
Am J Cancer Res, 2020 Dec 10; 10(11). PMID: 33294255    Free PMC article.
Eomes promotes esophageal carcinoma progression by recruiting Treg cells through the CCL20-CCR6 pathway.
Jingyao Lian, Saisai Liu, +4 authors, Yi Zhang.
Cancer Sci, 2020 Oct 29; 112(1). PMID: 33113266    Free PMC article.
EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia.
Philipp M Roessner, Laura Llaó Cid, +15 authors, Martina Seiffert.
Leukemia, 2021 Feb 03; 35(8). PMID: 33526861    Free PMC article.
B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes.
Gihoon You, Yangsoon Lee, +18 authors, Seung-Woo Lee.
Sci Adv, 2021 Feb 02; 7(3). PMID: 33523913    Free PMC article.
EOMES is essential for antitumor activity of CD8+ T cells in chronic lymphocytic leukemia.
Laura Llaó-Cid, Philipp M Roessner, +10 authors, Martina Seiffert.
Leukemia, 2021 Mar 19; 35(11). PMID: 33731848    Free PMC article.
A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy.
Shannon K Oda, Kristin G Anderson, +8 authors, Philip D Greenberg.
J Exp Med, 2020 Aug 30; 217(12). PMID: 32860705    Free PMC article.
Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function.
Jayati Basu, Bernardo S Reis, +14 authors, Dietmar J Kappes.
Nat Immunol, 2021 Jul 28; 22(8). PMID: 34312548    Free PMC article.
EZH2 Inhibition Compromises α4-1BB-Mediated Antitumor Efficacy by Reducing the Survival and Effector Programming of CD8+ T Cells.
Christopher J Stairiker, Sophia Xiao Pfister, +7 authors, Shahram Salek-Ardakani.
Front Immunol, 2021 Dec 21; 12. PMID: 34925340    Free PMC article.
Bona Fide Th17 Cells without Th1 Functional Plasticity Protect against Influenza.
Kunal Dhume, Caroline M Finn, +7 authors, Karl Kai McKinstry.
J Immunol, 2022 Mar 27; 208(8). PMID: 35338093    Free PMC article.