Identification of a Novel Eomesodermin Expressing T cell Subset

41BB (CD137) is a costimulatory receptor transiently upregulated on T cells following activation.  41BB is activated by its ligand 41BBL (TNFSF9), a TNF receptor superfamily member expressed by activated antigen presenting cells and anti-41BB agonistic antibodies are in clinical trials for cancer immunotherapy.  In a recent article in The Journal of Experimental Medicine, Curran et. al demonstrate that 41BB activation of T cells leads to the generation of a novel subset of CD4+ and CD8+ T cells dependant on the master transcription factor Eomesodermin (Eomes).

describe the imageActivation of 41BB on T cells leads to enhanced T cell survival.  Anti-41BB-agonistic antibodies have demonstrated significant anti-tumor activity in mice by enhancing anti-tumor cytotoxic T cell responses.  Thus, there are currently several clinical trials underway exploring the efficacy of anti-41BB-agonist antibodies in several types of cancers, including melanoma, renal carcinoma, ovarian cancer, and lymphoma.  In a previous study by the same group (Curran et. al, PLoS One, 2011), an observation was made that a unique subset of T cells infiltrated B16 melanoma tumors in mice after anti-41BB-agonistic antibody treatment.  These T cells expressed the inhibitory receptor KLRG1, and elicited strong anti-tumor activity.  Thus, in the current study, the authors sought to further characterize this T cell subset in mice.

To define the phenotype and functions of tumor-associated KLRG1+ versus KLRG1T cells types, T cells were isolated from B16 tumors established in mice, following treatment with anti-41BB antibodies plus irradiated Flt3-ligand–expressing B16 cells (FVAX) or FVAX alone. The addition of FVAX further enhanced the tumor-infiltrating frequency of KLRG1+ T cells elicited by anti-41BB antibodies.  Gene expression analysis revealed that KLRG1+ CD4+ and CD8+ T cells expressed significantly higher levels of cytoxicity genes: multiple granzymes, perforin, and FasL, than KLRG1T cells.  In vitro cytotoxicity assays with B16 melanoma cell targets demonstrated enhanced killing capacity of KLRG1+ compared with KLRG1 CD4+ and CD8+ T cells.

Superior cytotoxic functions are generally associated with CD4+ TH1 and CD8+ TC1 T cell subsets, dependant on the transcription factor T-bet (TBX21).  However, analysis of expression of the known master transcription factors governing different T cell subsets, found that expression of Eomes but not T-bet was elevated in KLRG1+ T cells.  Runx3 expression was also slightly elevated in KLRG1+ versus KLRG1T cells.  Furthermore, transgenic mice lacking Eomes expression in CD4+ cells (CD4-CRE/Eomesflox/flox) did not develop tumor-infiltrating KLRG1+ T cells after anti-41BB antibody treatment, demonstrating the necessity of Eomes for development of these cells, even when Eomes expression is only absent in the CD4+ T cell compartment.  Thus, these novel subsets of KLRG1+ T cells were termed CD4+ THEO and CD8+ TCEO T cells.

Interestingly, KLRG1+ T cells play a role not only in anti-tumor immunity, but were induced and found at significant levels in spleens and livers from mice infected with Listeria Monocytogenes or LCMV.

As this is a newly described T cell subset, many questions remain.  However, most relevant is whether equivalents of these cells exist in humans, and the roles they play in human diseases.

Further Reading:

Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin.  Curran MA, Geiger TL, Montalvo W, Kim M, Reiner SL, Al-Shamkhani A, Sun JC, Allison JP. J Exp Med. 2013 Apr 8;210(4):743-55.

Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production.  Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. PLoS One. 2011 Apr 29;6(4):e19499.

Immunotherapy of cancer with 4-1BB.  Vinay DS, Kwon BS. Mol Cancer Ther. 2012 May;11(5):1062-70. doi: 10.1158/1535-7163.MCT-11-0677. Epub 2012 Apr 24.

Immune regulation by 4-1BB and 4-1BBL: complexities and challenges.  Wang C, Lin GH, McPherson AJ, Watts TH. Immunol Rev. 2009 May;229(1):192-215.

About Andrea

Andrea Miyahira is currently a post-doctoral fellow at the Beckman Research Institute of the City of Hope, in Duarte, CA. She received her Ph.D. from UCLA and her main research interest is in the field of cancer immunology.

  • Matthew Marple

    Great article !