. 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 
  • PMID: 25086175
  •     62 References
  •     66 citations


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.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
mTOR regulates memory CD8 T-cell differentiation.
Koichi Araki, Alexandra P Turner, +5 authors, Rafi Ahmed.
Nature, 2009 Jun 23; 460(7251). PMID: 19543266    Free PMC article.
Highly Cited.
Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.
Nobuhiro Nakamoto, Hyosun Cho, +8 authors, Kyong-Mi Chang.
PLoS Pathog, 2009 Feb 28; 5(2). PMID: 19247441    Free PMC article.
Highly Cited.
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L Topalian, F Stephen Hodi, +27 authors, Mario Sznol.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658127    Free PMC article.
Highly Cited.
Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies.
Yannick Bulliard, Rose Jolicoeur, +6 authors, Jennifer L Brogdon.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897982    Free PMC article.
Highly Cited.
Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity.
Rachel H McMahan, Lucy Golden-Mason, +5 authors, Hugo R Rosen.
J Clin Invest, 2010 Nov 19; 120(12). PMID: 21084749    Free PMC article.
Highly Cited.
Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.
Julien Fourcade, Zhaojun Sun, +6 authors, Hassane M Zarour.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819923    Free PMC article.
Highly Cited.
The role of LAT in increased CD8+ T cell exhaustion in trigeminal ganglia of mice latently infected with herpes simplex virus 1.
Sariah J Allen, Pedram Hamrah, +12 authors, Homayon Ghiasi.
J Virol, 2011 Feb 11; 85(9). PMID: 21307196    Free PMC article.
SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.
Jens M Chemnitz, Richard V Parry, +2 authors, James L Riley.
J Immunol, 2004 Jul 09; 173(2). PMID: 15240681
Highly Cited.
Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.
Shigeki Chiba, Muhammad Baghdadi, +12 authors, Masahisa Jinushi.
Nat Immunol, 2012 Jul 31; 13(9). PMID: 22842346    Free PMC article.
Highly Cited.
Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions.
Yueqin Qiu, Jianbo Chen, +15 authors, Zheng W Chen.
PLoS Pathog, 2012 Nov 13; 8(11). PMID: 23144609    Free PMC article.
TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression.
Xin Gao, Yibei Zhu, +7 authors, Binfeng Lu.
PLoS One, 2012 Mar 01; 7(2). PMID: 22363469    Free PMC article.
Highly Cited.
Emerging Tim-3 functions in antimicrobial and tumor immunity.
Kaori Sakuishi, Pushpa Jayaraman, +2 authors, Vijay K Kuchroo.
Trends Immunol, 2011 Jun 24; 32(8). PMID: 21697013    Free PMC article.
Highly Cited. Review.
Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors.
Shin Foong Ngiow, Bianca von Scheidt, +3 authors, Mark J Smyth.
Cancer Res, 2011 Mar 25; 71(10). PMID: 21430066
Highly Cited.
Restoring function in exhausted CD8 T cells during chronic viral infection.
Daniel L Barber, E John Wherry, +5 authors, Rafi Ahmed.
Nature, 2005 Dec 31; 439(7077). PMID: 16382236
Highly Cited.
Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection.
Jacob V Gorman, Gabriel Starbeck-Miller, +4 authors, John D Colgan.
J Immunol, 2014 Feb 26; 192(7). PMID: 24567532    Free PMC article.
Monoclonal antibody TGN1412 trial failure explained by species differences in CD28 expression on CD4+ effector memory T-cells.
D Eastwood, L Findlay, +6 authors, R Stebbings.
Br J Pharmacol, 2010 Oct 01; 161(3). PMID: 20880392    Free PMC article.
Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412.
Ganesh Suntharalingam, Meghan R Perry, +4 authors, Nicki Panoskaltsis.
N Engl J Med, 2006 Aug 16; 355(10). PMID: 16908486
Highly Cited.
T cell exhaustion.
E John Wherry.
Nat Immunol, 2011 Jul 09; 12(6). PMID: 21739672
Highly Cited. Review.
mTOR signaling in growth control and disease.
Mathieu Laplante, David M Sabatini.
Cell, 2012 Apr 17; 149(2). PMID: 22500797    Free PMC article.
Highly Cited. Review.
Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.
Shawn D Blackburn, Haina Shin, +7 authors, E John Wherry.
Nat Immunol, 2008 Dec 02; 10(1). PMID: 19043418    Free PMC article.
Highly Cited.
Signal integration by Akt regulates CD8 T cell effector and memory differentiation.
Eui Ho Kim, Jeremy A Sullivan, +4 authors, M Suresh.
J Immunol, 2012 Apr 03; 188(9). PMID: 22467649    Free PMC article.
Highly Cited.
Redefining chronic viral infection.
Herbert W Virgin, E John Wherry, Rafi Ahmed.
Cell, 2009 Jul 15; 138(1). PMID: 19596234
Highly Cited. Review.
TIM-1 and TIM-3 enhancement of Th2 cytokine production by mast cells.
Susumu Nakae, Motoyasu Iikura, +5 authors, Stephen J Galli.
Blood, 2007 Jul 11; 110(7). PMID: 17620455    Free PMC article.
Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell.
Kirsten Richter, Thomas Brocker, Annette Oxenius.
Eur J Immunol, 2012 Jun 02; 42(9). PMID: 22653665
Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells.
Lucy Golden-Mason, Brent E Palmer, +7 authors, Hugo R Rosen.
J Virol, 2009 Jul 10; 83(18). PMID: 19587053    Free PMC article.
Highly Cited.
Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells.
Ana C Anderson, David E Anderson, +11 authors, David A Hafler.
Science, 2007 Nov 17; 318(5853). PMID: 18006747
Highly Cited.
The storm has cleared: lessons from the CD28 superagonist TGN1412 trial.
Thomas Hünig.
Nat Rev Immunol, 2012 Apr 11; 12(5). PMID: 22487653
Jurkat T cells and development of the T-cell receptor signalling paradigm.
Robert T Abraham, Arthur Weiss.
Nat Rev Immunol, 2004 Apr 02; 4(4). PMID: 15057788
Highly Cited. Review.
PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.
Alena Gros, Paul F Robbins, +13 authors, Steven A Rosenberg.
J Clin Invest, 2014 Mar 29; 124(5). PMID: 24667641    Free PMC article.
Highly Cited.
IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma.
Zhi-Zhang Yang, Deanna M Grote, +5 authors, Stephen M Ansell.
J Clin Invest, 2012 Mar 20; 122(4). PMID: 22426209    Free PMC article.
Highly Cited.
Suppression of HIV replication by antiretroviral therapy reduces TIM-3 expression on HIV-specific CD8(+) T cells.
Afework Kassu, Roland A Marcus, +2 authors, Brent E Palmer.
AIDS Res Hum Retroviruses, 2010 Sep 24; 27(1). PMID: 20860535
Storm forecasting: additional lessons from the CD28 superagonist TGN1412 trial.
Christopher Horvath, Laura Andrews, +14 authors, James D Green.
Nat Rev Immunol, 2012 Sep 04; 12(10). PMID: 22941443
Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival.
Timothy W Hand, Weiguo Cui, +5 authors, Susan M Kaech.
Proc Natl Acad Sci U S A, 2010 Sep 09; 107(38). PMID: 20823247    Free PMC article.
Highly Cited.
Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism.
Andrew N Macintyre, David Finlay, +6 authors, Doreen A Cantrell.
Immunity, 2011 Feb 08; 34(2). PMID: 21295499    Free PMC article.
Highly Cited.
A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9.
Philipp S van de Weyer, Michael Muehlfeit, +3 authors, E Wolfgang Kuehn.
Biochem Biophys Res Commun, 2006 Oct 31; 351(2). PMID: 17069754
PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.
Cheryl L Day, Daniel E Kaufmann, +19 authors, Bruce D Walker.
Nature, 2006 Aug 22; 443(7109). PMID: 16921384
Highly Cited.
Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes.
Ying Zhang, Cheng J Ma, +4 authors, Zhi Q Yao.
J Leukoc Biol, 2011 Aug 17; 91(2). PMID: 21844165    Free PMC article.
Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection.
Hyun-Tak Jin, Ana C Anderson, +6 authors, Rafi Ahmed.
Proc Natl Acad Sci U S A, 2010 Aug 04; 107(33). PMID: 20679213    Free PMC article.
Highly Cited.
The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin.
Rajesh R Rao, Qingsheng Li, Kunle Odunsi, Protul A Shrikant.
Immunity, 2010 Jan 12; 32(1). PMID: 20060330    Free PMC article.
Highly Cited.
Tim-3: an activation marker and activation limiter of innate immune cells.
Gencheng Han, Guojiang Chen, Beifen Shen, Yan Li.
Front Immunol, 2013 Dec 18; 4. PMID: 24339828    Free PMC article.
Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways.
Judong Lee, Ee Wern Su, +6 authors, Lawrence P Kane.
Mol Cell Biol, 2011 Aug 03; 31(19). PMID: 21807895    Free PMC article.
Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection.
Afework Kassu, Roland A Marcus, +6 authors, Brent E Palmer.
J Immunol, 2010 Jul 27; 185(5). PMID: 20656923    Free PMC article.
CD8 T cell dysfunction during chronic viral infection.
Haina Shin, E John Wherry.
Curr Opin Immunol, 2007 Jul 28; 19(4). PMID: 17656078
Highly Cited. Review.
T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response.
Xiaomei Yang, Xingwei Jiang, +16 authors, Gencheng Han.
J Immunol, 2013 Feb 01; 190(5). PMID: 23365080
Tolerance and exhaustion: defining mechanisms of T cell dysfunction.
Andrea Schietinger, Philip D Greenberg.
Trends Immunol, 2013 Nov 12; 35(2). PMID: 24210163    Free PMC article.
Highly Cited. Review.
The Tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with Mycobacterium tuberculosis.
Isabel Sada-Ovalle, Leslie Chávez-Galán, +6 authors, Samuel M Behar.
J Immunol, 2012 Nov 28; 189(12). PMID: 23180819    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Tim-3 negatively regulates IL-12 expression by monocytes in HCV infection.
Ying Zhang, Cheng J Ma, +5 authors, Zhi Q Yao.
PLoS One, 2011 Jun 04; 6(5). PMID: 21637332    Free PMC article.
Tim3 binding to galectin-9 stimulates antimicrobial immunity.
Pushpa Jayaraman, Isabel Sada-Ovalle, +5 authors, Samuel M Behar.
J Exp Med, 2010 Oct 13; 207(11). PMID: 20937702    Free PMC article.
TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer.
Kaori Sakuishi, Shin Foong Ngiow, +4 authors, Ana C Anderson.
Oncoimmunology, 2013 Jun 05; 2(4). PMID: 23734331    Free PMC article.
Highly Cited.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
Kaori Sakuishi, Lionel Apetoh, +3 authors, Ana C Anderson.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    Free PMC article.
Highly Cited.
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.
Carrie L Lucas, Hye Sun Kuehn, +25 authors, Gulbu Uzel.
Nat Immunol, 2013 Oct 30; 15(1). PMID: 24165795    Free PMC article.
Highly Cited.
Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma.
Evan J Lipson, Charles G Drake.
Clin Cancer Res, 2011 Sep 09; 17(22). PMID: 21900389    Free PMC article.
Highly Cited. Review.
Inhibitory receptors on lymphocytes: insights from infections.
Pamela M Odorizzi, E John Wherry.
J Immunol, 2012 Mar 24; 188(7). PMID: 22442493    Free PMC article.
Mechanisms of immune evasion by tumors.
Charles G Drake, Elizabeth Jaffee, Drew M Pardoll.
Adv Immunol, 2006 May 30; 90. PMID: 16730261
Highly Cited. Review.
High antigen levels are the cause of T cell exhaustion during chronic viral infection.
Scott N Mueller, Rafi Ahmed.
Proc Natl Acad Sci U S A, 2009 May 13; 106(21). PMID: 19433785    Free PMC article.
Highly Cited.
Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
Manu Rangachari, Chen Zhu, +13 authors, Vijay K Kuchroo.
Nat Med, 2012 Aug 07; 18(9). PMID: 22863785    Free PMC article.
Highly Cited.
Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
Omid Hamid, Caroline Robert, +23 authors, Antoni Ribas.
N Engl J Med, 2013 Jun 04; 369(2). PMID: 23724846    Free PMC article.
Highly Cited.
T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases.
Kiera L Clayton, Matthew S Haaland, +4 authors, Mario A Ostrowski.
J Immunol, 2013 Dec 18; 192(2). PMID: 24337741    Free PMC article.
Transcription factor regulation of CD8+ T-cell memory and exhaustion.
Jill M Angelosanto, E John Wherry.
Immunol Rev, 2010 Jul 20; 236. PMID: 20636816
Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection.
R Brad Jones, Lishomwa C Ndhlovu, +24 authors, Mario A Ostrowski.
J Exp Med, 2008 Nov 13; 205(12). PMID: 19001139    Free PMC article.
Highly Cited.
Immune checkpoint inhibitors in clinical trials.
Elad Sharon, Howard Streicher, Priscila Goncalves, Helen X Chen.
Chin J Cancer, 2014 Sep 06; 33(9). PMID: 25189716    Free PMC article.
T cell exhaustion during persistent viral infections.
Shannon M Kahan, E John Wherry, Allan J Zajac.
Virology, 2015 Jan 27; 479-480. PMID: 25620767    Free PMC article.
Highly Cited. Review.
Leveraging Cancer Therapeutics for the HIV Cure Agenda: Current Status and Future Directions.
Mark N Polizzotto, Grace Chen, Randall L Tressler, Catherine Godfrey.
Drugs, 2015 Aug 01; 75(13). PMID: 26224205    Free PMC article.
Microenvironment abnormalities and lymphomagenesis: Immunological aspects.
Joseph G Taylor, John G Gribben.
Semin Cancer Biol, 2015 Aug 02; 34. PMID: 26232774    Free PMC article.
Immunology and Immunotherapy of Head and Neck Cancer.
Robert L Ferris.
J Clin Oncol, 2015 Sep 10; 33(29). PMID: 26351330    Free PMC article.
Highly Cited. Review.
Targeting Transcriptional Regulators of CD8+ T Cell Dysfunction to Boost Anti-Tumor Immunity.
Katherine A Waugh, Sonia M Leach, Jill E Slansky.
Vaccines (Basel), 2015 Sep 24; 3(3). PMID: 26393659    Free PMC article.
Immunomodulation: checkpoint blockade etc.
William T Curry, Michael Lim.
Neuro Oncol, 2015 Oct 31; 17 Suppl 7. PMID: 26516223    Free PMC article.
Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.
Binh L Phong, Lyndsay Avery, +4 authors, Lawrence P Kane.
J Exp Med, 2015 Nov 26; 212(13). PMID: 26598760    Free PMC article.
Characterization of age-associated exhausted CD8⁺ T cells defined by increased expression of Tim-3 and PD-1.
Kyoo-A Lee, Kwang-Soo Shin, +5 authors, Chang-Yuil Kang.
Aging Cell, 2016 Jan 12; 15(2). PMID: 26750587    Free PMC article.
Cancer immunoprevention.
Olivera J Finn, Pamela L Beatty.
Curr Opin Immunol, 2016 Jan 23; 39. PMID: 26799207    Free PMC article.
Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer.
R B Birge, S Boeltz, +13 authors, M Herrmann.
Cell Death Differ, 2016 Feb 27; 23(6). PMID: 26915293    Free PMC article.
Highly Cited. Review.
Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.
John J Erickson, Meredith C Rogers, +2 authors, John V Williams.
J Immunol, 2016 Jun 05; 197(1). PMID: 27259857    Free PMC article.
Avidity characterization of genetically engineered T-cells with novel and established approaches.
Victoria Hillerdal, Vanessa F Boura, +2 authors, Magnus Essand.
BMC Immunol, 2016 Jul 15; 17(1). PMID: 27411667    Free PMC article.
Exhaustion of Activated CD8 T Cells Predicts Disease Progression in Primary HIV-1 Infection.
Matthias Hoffmann, Nikos Pantazis, +16 authors, SPARTAC and CHERUB Investigators.
PLoS Pathog, 2016 Jul 16; 12(7). PMID: 27415828    Free PMC article.
Highly Cited.
Abnormal expression of Tim-3 antigen on peripheral blood T cells is associated with progressive disease in osteosarcoma patients.
Hongliang Liu, Liqiang Zhi, Ning Duan, Pengxiao Su.
FEBS Open Bio, 2016 Aug 16; 6(8). PMID: 27516959    Free PMC article.
KLRG1 restricts memory T cell antitumor immunity.
Lei Li, Shanshan Wan, +2 authors, Ende Zhao.
Oncotarget, 2016 Aug 25; 7(38). PMID: 27557510    Free PMC article.
PD-L1 expression on immune cells, but not on tumor cells, is a favorable prognostic factor for head and neck cancer patients.
Hye Ryun Kim, Sang-Jun Ha, +10 authors, Sun Och Yoon.
Sci Rep, 2016 Nov 15; 6. PMID: 27841362    Free PMC article.
Highly Cited.
Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk.
Jing Li, Gulidanna Shayan, +6 authors, Robert L Ferris.
Oncoimmunology, 2016 Nov 18; 5(10). PMID: 27853635    Free PMC article.
Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer.
Gulidanna Shayan, Raghvendra Srivastava, +3 authors, Robert L Ferris.
Oncoimmunology, 2017 Feb 16; 6(1). PMID: 28197389    Free PMC article.
Highly Cited.
TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action.
Wenwen Du, Min Yang, +5 authors, Binfeng Lu.
Int J Mol Sci, 2017 Mar 17; 18(3). PMID: 28300768    Free PMC article.
Modulation of Tim-3 Expression by Antigen-Dependent and -Independent Factors on T Cells from Patients with Chronic Hepatitis B Virus Infection.
Jie Dong, Xiao-Fei Yang, +7 authors, Jian-Qi Lian.
Front Cell Infect Microbiol, 2017 Apr 13; 7. PMID: 28401068    Free PMC article.
Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients.
Hyun-Bae Jie, Raghvendra M Srivastava, +3 authors, Robert L Ferris.
Cancer Immunol Res, 2017 Apr 15; 5(5). PMID: 28408386    Free PMC article.
Immunometabolic Regulations Mediated by Coinhibitory Receptors and Their Impact on T Cell Immune Responses.
Nikolaos Patsoukis, Jessica D Weaver, +3 authors, Vassiliki A Boussiotis.
Front Immunol, 2017 Apr 27; 8. PMID: 28443090    Free PMC article.
Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma.
Dirk Schadendorf, Paul Nghiem, +5 authors, Howard L Kaufman.
Oncoimmunology, 2017 Nov 11; 6(10). PMID: 29123950    Free PMC article.
TIM-3 Engagement Promotes Effector Memory T Cell Differentiation of Human Antigen-Specific CD8 T Cells by Activating mTORC1.
Nina Chi Sabins, Olesya Chornoguz, +8 authors, Sandra Santulli-Marotto.
J Immunol, 2017 Nov 12; 199(12). PMID: 29127145    Free PMC article.
Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling.
Isobel Okoye, Afshin Namdar, +2 authors, Shokrollah Elahi.
Oncotarget, 2017 Dec 13; 8(58). PMID: 29228684    Free PMC article.
Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis.
Michelle Fleury, Anna C Belkina, +6 authors, Hans Dooms.
Arthritis Rheumatol, 2017 Dec 16; 70(4). PMID: 29245183    Free PMC article.
T-cell immunoglobulin and mucin domain-containing protein-3 and galectin-9 protein expression: Potential prognostic significance in esophageal squamous cell carcinoma for Chinese patients.
Nan Hou, Jie Ma, +3 authors, Ling Mai.
Oncol Lett, 2018 Jan 19; 14(6). PMID: 29344243    Free PMC article.
Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion.
Lyndsay Avery, Jessica Filderman, Andrea L Szymczak-Workman, Lawrence P Kane.
Proc Natl Acad Sci U S A, 2018 Feb 22; 115(10). PMID: 29463725    Free PMC article.
Highly Cited.
Immune regulation by Tim-3.
Hridesh Banerjee, Lawrence P Kane.
F1000Res, 2018 Mar 22; 7. PMID: 29560265    Free PMC article.
Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim-3 and inducing nuclear translocation of Bat3 in HCC.
Jie Ji, Yin Yin, +6 authors, Beicheng Sun.
Cell Death Dis, 2018 May 01; 9(5). PMID: 29706626    Free PMC article.
Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.
Zhuqing Liu, Elizabeth L McMichael, +6 authors, Robert L Ferris.
Clin Cancer Res, 2018 May 02; 24(18). PMID: 29712685    Free PMC article.
Altered Expression of CD300a Inhibitory Receptor on CD4+ T Cells From Human Immunodeficiency Virus-1-Infected Patients: Association With Disease Progression Markers.
Joana Vitallé, Iñigo Terrén, +8 authors, Francisco Borrego.
Front Immunol, 2018 Aug 08; 9. PMID: 30083165    Free PMC article.
Influence of T Cell Coinhibitory Molecules on CD8+ Recall Responses.
Anna B Morris, Layne E Adams, Mandy L Ford.
Front Immunol, 2018 Aug 24; 9. PMID: 30135685    Free PMC article.
TLR Stimulation during T-cell Activation Lowers PD-1 Expression on CD8+ T Cells.
Christopher D Zahm, Viswa T Colluru, +2 authors, Douglas G McNeel.
Cancer Immunol Res, 2018 Sep 12; 6(11). PMID: 30201735    Free PMC article.
TIM-3, a promising target for cancer immunotherapy.
Yayi He, Jie Cao, +3 authors, Fred R Hirsch.
Onco Targets Ther, 2018 Nov 10; 11. PMID: 30410357    Free PMC article.
Highly Cited. Review.
Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation.
Pietro Merli, Ignazio Caruana, +16 authors, Franco Locatelli.
Haematologica, 2019 Feb 23; 104(11). PMID: 30792213    Free PMC article.
Immunosuppressive Tumor Microenvironment Status and Histological Grading of Endometrial Carcinoma.
Julie Antomarchi, Damien Ambrosetti, +6 authors, Heidy Schmid-Antomarchi.
Cancer Microenviron, 2019 May 28; 12(2-3). PMID: 31134527    Free PMC article.
Is There a Positive Side to T Cell Exhaustion?
Graham Pawelec.
Front Immunol, 2019 Feb 15; 10. PMID: 30761152    Free PMC article.
Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients.
Varun Sasidharan Nair, Salman M Toor, +8 authors, Eyad Elkord.
Vaccines (Basel), 2020 Feb 12; 8(1). PMID: 32041340    Free PMC article.
Cell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy.
Michael F Coleman, Alyssa J Cozzo, +2 authors, Stephen D Hursting.
Cancers (Basel), 2020 Apr 05; 12(4). PMID: 32244756    Free PMC article.
Heterogeneity of exhausted T cells in the tumor microenvironment is linked to patient survival following resection in hepatocellular carcinoma.
Fangming Liu, Weiren Liu, +9 authors, Duojiao Wu.
Oncoimmunology, 2020 May 20; 9(1). PMID: 32426177    Free PMC article.
Soluble Tim3 detection by time-resolved fluorescence immunoassay and its application in membranous nephropathy.
Ming Chen, Liang Wang, +5 authors, Zhigang Hu.
J Clin Lab Anal, 2020 Feb 23; 34(6). PMID: 32077157    Free PMC article.
Identification of FABP5 as an immunometabolic marker in human hepatocellular carcinoma.
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.
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.
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.
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.
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.
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.
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.
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.