Review
. 2014 Aug; 193(4):1525-30.
doi: 10.4049/jimmunol.1400557.

Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion

Robert L Ferris 1 Binfeng Lu 2 Lawrence P Kane 3 
Affiliations
  • PMID: 25086175
  •     62 References
  •     66 citations

Abstract

T cell exhaustion is thought to be a natural mechanism for limiting immune pathology, although it may be desirable to circumvent this mechanism to help eliminate viral reservoirs or tumors. Although there are no definitive markers, a fingerprint for exhausted T cells has been described that includes the transmembrane proteins PD-1, LAG3, and Tim-3. However, apart from the recruitment of tyrosine phosphatases to PD-1, little is known about the biochemical mechanisms by which these proteins contribute to the development or maintenance of exhaustion. Tim-3 contains no known motifs for the recruitment of inhibitory phosphatases, but it may actually increase signaling downstream of TCR/CD3, at least under acute conditions. Other studies showed that T cell exhaustion results from chronic stimulation that extends the effector phase of T cell activation, at the expense of T cell memory. We suggest that Tim-3 may contribute to T cell exhaustion by enhancing TCR-signaling pathways.

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Fangming Liu, Weiren Liu, +13 authors, Duojiao Wu.
J Immunother Cancer, 2020 Jul 03; 8(2). PMID: 32611686    Free PMC article.
Therapeutic targeting of immune checkpoints with small molecule inhibitors.
Wade M Smith, Ian J Purvis, +7 authors, Swapna Asuthkar.
Am J Transl Res, 2019 Mar 23; 11(2). PMID: 30899360    Free PMC article.
Review.
Costimulatory and coinhibitory immune checkpoint receptors in head and neck cancer: unleashing immune responses through therapeutic combinations.
Ruth J Davis, Robert L Ferris, Nicole C Schmitt.
Cancers Head Neck, 2016 Oct 01; 1. PMID: 31093342    Free PMC article.
Review.
Monitoring Patient Response to Pembrolizumab With Peripheral Blood Exhaustion Marker Profiles.
Moira Graves, Giovana CelliMarchett, +4 authors, Nikola A Bowden.
Front Med (Lausanne), 2019 Jun 14; 6. PMID: 31192212    Free PMC article.
TIM-3 and CEACAM1 do not interact in cis and in trans.
Annika De Sousa Linhares, Florian Kellner, +5 authors, Peter Steinberger.
Eur J Immunol, 2020 Mar 31; 50(8). PMID: 32222966    Free PMC article.
TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation.
Tram N Dao, Sagar Utturkar, Nadia Atallah Lanman, Sandro Matosevic.
Cancers (Basel), 2020 Aug 30; 12(9). PMID: 32858904    Free PMC article.
Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer.
Namrata Khurana, Paarth B Dodhiawala, Ashenafi Bulle, Kian-Huat Lim.
Cancers (Basel), 2020 Sep 24; 12(9). PMID: 32961746    Free PMC article.
Review.
The Confounders of Cancer Immunotherapy: Roles of Lifestyle, Metabolic Disorders and Sociological Factors.
Ravindra Pramod Deshpande, Sambad Sharma, Kounosuke Watabe.
Cancers (Basel), 2020 Oct 21; 12(10). PMID: 33076303    Free PMC article.
Review.
Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.
Brian Koss, Bradley D Shields, +16 authors, Alan J Tackett.
Cancer Res, 2020 Oct 03; 80(21). PMID: 33004350    Free PMC article.
Immune Checkpoint Receptors Tim-3 and PD-1 Regulate Monocyte and T Lymphocyte Function in Septic Patients.
Qi Xia, Li Wei, +3 authors, Yi Zhang.
Mediators Inflamm, 2019 Jan 01; 2018. PMID: 30595665    Free PMC article.
Forest Bathing Always Makes Sense: Blood Pressure-Lowering and Immune System-Balancing Effects in Late Spring and Winter in Central Europe.
Agnes Peterfalvi, Matyas Meggyes, +4 authors, Laszlo Szereday.
Int J Environ Res Public Health, 2021 Mar 07; 18(4). PMID: 33672536    Free PMC article.
PD-1, TIM-3, and LAG-3 Expression in T Cells in a Patient with Recurrent Ossifying Fibroma: A Case Report.
Alejandro García-Muñoz, Nayeli Goreti Nieto-Velázquez, +7 authors, Mario Adán Moreno-Eutimio.
Int J Mol Cell Med, 2021 Mar 11; 9(4). PMID: 33688488    Free PMC article.
TIM-3 drives temporal differences in restimulation-induced cell death sensitivity in effector CD8+ T cells in conjunction with CEACAM1.
Camille M Lake, Kelsey Voss, +4 authors, Andrew L Snow.
Cell Death Dis, 2021 Apr 16; 12(4). PMID: 33854046    Free PMC article.
Tim-3 is dispensable for allergic inflammation and respiratory tolerance in experimental asthma.
Carolin Boehne, Ann-Kathrin Behrendt, +4 authors, Gesine Hansen.
PLoS One, 2021 Apr 07; 16(4). PMID: 33822811    Free PMC article.
Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome.
Asima Abidi, Mark A J Gorris, +7 authors, I Jolanda M de Vries.
Cancers (Basel), 2021 Jun 03; 13(10). PMID: 34067951    Free PMC article.
Review.
Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment.
Hyung-Seok Kim, Chi Young Chang, +6 authors, Eun Jung Park.
Cancer Res, 2020 Feb 26; 80(9). PMID: 32094297    Free PMC article.
Immune Aging and Immunotherapy in Cancer.
Melanie Kaiser, Maria Donatella Semeraro, +3 authors, Wilfried Renner.
Int J Mol Sci, 2021 Jul 03; 22(13). PMID: 34209842    Free PMC article.
Review.
The HIV-1 accessory protein Nef increases surface expression of the checkpoint receptor Tim-3 in infected CD4+ T cells.
Rajesh Abraham Jacob, Cassandra R Edgar, +8 authors, Jimmy D Dikeakos.
J Biol Chem, 2021 Aug 07; 297(3). PMID: 34358561    Free PMC article.
Expression of Tim-3 drives phenotypic and functional changes in Treg cells in secondary lymphoid organs and the tumor microenvironment.
Hridesh Banerjee, Hector Nieves-Rosado, +9 authors, Lawrence P Kane.
Cell Rep, 2021 Sep 16; 36(11). PMID: 34525351    Free PMC article.
Phosphatidylserine binding directly regulates TIM-3 function.
Courtney M Smith, Alice Li, Nithya Krishnamurthy, Mark A Lemmon.
Biochem J, 2021 Aug 27; 478(17). PMID: 34435619    Free PMC article.
TIM-3 in Leukemia; Immune Response and Beyond.
Mahnaz Rezaei, Jiaxiong Tan, +2 authors, Mazdak Ganjalikhani-Hakemi.
Front Oncol, 2021 Oct 19; 11. PMID: 34660319    Free PMC article.
Review.
Adenosine 2A receptor and TIM3 suppress cytolytic killing of tumor cells via cytoskeletal polarization.
Grace L Edmunds, Carissa C W Wong, +6 authors, David J Morgan.
Commun Biol, 2022 Jan 12; 5(1). PMID: 35013519    Free PMC article.
Toll-like receptor agonist combinations augment mouse T-cell anti-tumor immunity via IL-12- and interferon ß-mediated suppression of immune checkpoint receptor expression.
Donghwan Jeon, Douglas G McNeel.
Oncoimmunology, 2022 Mar 29; 11(1). PMID: 35340661    Free PMC article.