Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 12;58(8):1966-1983.e10.
doi: 10.1016/j.immuni.2025.06.001. Epub 2025 Jul 7.

The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells

Etienne Humblin  1 , Isabel Korpas  2 , Nataliya Prokhnevska  2 , Abishek Vaidya  2 , Dan Filipescu  3 , Jiahua Lu  4 , Verena van der Heide  2 , Carlos Alberto de Carvalho Fraga  5 , Tesia Bobrowski  6 , Adam Marks  7 , Matthew D Park  2 , Helder I Nakaya  8 , Emily Bernstein  3 , Brian D Brown  9 , Amaia Lujambio  10 , David Dominguez-Sola  11 , Brad R Rosenberg  6 , Alice O Kamphorst  12
Affiliations

The costimulatory molecule ICOS limits memory-like properties and function of exhausted PD-1+CD8+ T cells

Etienne Humblin et al. Immunity. .

Abstract

During persistent antigen stimulation, CD8+ T cell responses are maintained by progenitor exhausted CD8+ T (Tpex) cells. Tpex cells respond to blockade of the inhibitory receptor programmed cell death-1 (PD-1), and regulation of their differentiation is critical for immunotherapies. Tpex cells highly express inducible costimulator (ICOS), but how ICOS modulates PD-1+CD8+ T cells is not clear. During chronic infection, intrinsic ICOS deficiency increased number and quality of virus-specific CD8+ T cells. Loss of ICOS potentiated activity of the transcription factor forkhead box O1 (FoxO1) and memory-like features of Tpex cells. ICOS-deficient Tpex cells were poised to generate effecor-like cells with improved survival and cytokine production. ICOS-ligand (ICOSL) blockade expanded effector-like PD-1+CD8+ T cells, reduced viral load, and improved response to PD-1 blockade. Similarly, in a mouse model of hepatocellular carcinoma, ICOS inhibition enhanced tumor-specific CD8+ T cell responses and tumor control by PD-1 blockade. Overall, we show that sustained ICOS costimulation limits CD8+ T cell responses during chronic antigen exposure.

Keywords: CD8(+) T cells; FoxO1; ICOS; LCMV; PD-1; T cell differentiation; costimulation; exhaustion; immunotherapy; progenitor exhausted.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

Update of

References

    1. Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, and Ahmed R. (2018). CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med 69, 301–318. 10.1146/annurev-med-012017-043208. - DOI - PubMed
    1. McLane LM., Abdel-Hakeem MS., and Wherry EJ. (2019). CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol 37, 457–495. 10.1146/annurev-immunol-041015-055318. - DOI - PubMed
    1. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Nasti TH, Sharpe AH, et al. (2016). Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421. 10.1038/nature19330. - DOI - PMC - PubMed
    1. Wu T, Ji Y, Moseman EA, Xu HC, Manglani M, Kirby M, Anderson SM, Handon R, Kenyon E, Elkahloun A, et al. (2016). The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci Immunol 1. 10.1126/sciimmunol.aai8593. - DOI - PMC - PubMed
    1. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, et al. (2016). T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity 45, 415–427. 10.1016/j.immuni.2016.07.021. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources