TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes
IntroductionChronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabet...
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| Format: | Article |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1370907/full |
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| author | Prerak Trivedi Gaurang Jhala David J. De George David J. De George Chris Chiu Claudia Selck Claudia Selck Tingting Ge Tingting Ge Tara Catterall Lorraine Elkerbout Louis Boon Nicole Joller Thomas W. Kay Thomas W. Kay Helen E. Thomas Helen E. Thomas Balasubramanian Krishnamurthy Balasubramanian Krishnamurthy |
| author_facet | Prerak Trivedi Gaurang Jhala David J. De George David J. De George Chris Chiu Claudia Selck Claudia Selck Tingting Ge Tingting Ge Tara Catterall Lorraine Elkerbout Louis Boon Nicole Joller Thomas W. Kay Thomas W. Kay Helen E. Thomas Helen E. Thomas Balasubramanian Krishnamurthy Balasubramanian Krishnamurthy |
| author_sort | Prerak Trivedi |
| collection | DOAJ |
| description | IntroductionChronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function.MethodsThe phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody.ResultsWe show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice. DiscussionThese results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes. |
| first_indexed | 2024-04-25T00:38:16Z |
| format | Article |
| id | doaj.art-0e2a9e262b5049768e050d08ba434b1c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-25T00:38:16Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-0e2a9e262b5049768e050d08ba434b1c2024-03-12T12:30:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-03-011510.3389/fimmu.2024.13709071370907TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetesPrerak Trivedi0Gaurang Jhala1David J. De George2David J. De George3Chris Chiu4Claudia Selck5Claudia Selck6Tingting Ge7Tingting Ge8Tara Catterall9Lorraine Elkerbout10Louis Boon11Nicole Joller12Thomas W. Kay13Thomas W. Kay14Helen E. Thomas15Helen E. Thomas16Balasubramanian Krishnamurthy17Balasubramanian Krishnamurthy18Immunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaJJP Biologics, Warsaw, PolandDepartment of Quantitative Biomedicine, University of Zurich, Zurich, SwitzerlandImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaImmunology and Diabetes Unit, St Vincent’s Institute, Fitzroy, VIC, AustraliaDepartment of Medicine, St Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, AustraliaIntroductionChronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function.MethodsThe phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody.ResultsWe show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice. DiscussionThese results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1370907/fulltype 1 diabetesTIGITCD8+ T cellimmune checkpointNOD mouse |
| spellingShingle | Prerak Trivedi Gaurang Jhala David J. De George David J. De George Chris Chiu Claudia Selck Claudia Selck Tingting Ge Tingting Ge Tara Catterall Lorraine Elkerbout Louis Boon Nicole Joller Thomas W. Kay Thomas W. Kay Helen E. Thomas Helen E. Thomas Balasubramanian Krishnamurthy Balasubramanian Krishnamurthy TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes Frontiers in Immunology type 1 diabetes TIGIT CD8+ T cell immune checkpoint NOD mouse |
| title | TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes |
| title_full | TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes |
| title_fullStr | TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes |
| title_full_unstemmed | TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes |
| title_short | TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes |
| title_sort | tigit acts as an immune checkpoint upon inhibition of pd1 signaling in autoimmune diabetes |
| topic | type 1 diabetes TIGIT CD8+ T cell immune checkpoint NOD mouse |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1370907/full |
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