MERTK on mononuclear phagocytes regulates T cell antigen recognition at autoimmune and tumor sites

Understanding mechanisms of immune regulation is key to developing immunotherapies for autoimmunity and cancer. We examined the role of mononuclear phagocytes during peripheral T cell regulation in type 1 diabetes and melanoma. MERTK expression and activity in mononuclear phagocytes in the pancreatic islets promoted islet T cell regulation, resulting in reduced sensitivity of T cell scanning for cognate antigen in prediabetic islets. MERTK-dependent regulation led to reduced T cell activation and effector function at the disease site in islets and prevented rapid progression of type 1 diabetes. In human islets, MERTK-expressing cells were increased in remaining insulin-containing islets of type 1 diabetic patients, suggesting that MERTK protects islets from autoimmune destruction. MERTK also regulated T cell arrest in melanoma tumors. These data indicate that MERTK signaling in mononuclear phagocytes drives T cell regulation at inflammatory disease sites in peripheral tissues through a mechanism that reduces the sensitivity of scanning for antigen leading to reduced responsiveness to antigen.

Download Full-text

Mononuclear phagocytes drive Mertk-dependent T cell regulation at autoimmune and tumor sites

10.1101/687061 ◽

2019 ◽

Author(s):

Robin S. Lindsay ◽

Kristen E. Dew ◽

Erika Rodriguez ◽

Jennifer C. Whitesell ◽

Dayna Tracy ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Phagocytes ◽

Diabetic Patients ◽

Cell Regulation ◽

Peripheral Tissues ◽

Disease Site ◽

T Cell Regulation ◽

Cell Arrest

AbstractUnderstanding mechanisms of immune regulation is key to developing effective immunotherapies for autoimmunity and cancer; however, many regulatory mechanisms have not been elucidated. By analyzing T cell motility and activation at the disease site as well as disease progression, we examined the role of mononuclear phagocytes in driving regulation of effector T cells in type 1 diabetes and melanoma. We report that mononuclear phagocytes in the islets impair T cell responsiveness to antigen by preventing antigen-mediated T cell arrest. Mononuclear phagocytes in the autoimmune lesion express the TAM family receptor tyrosine kinase Mertk which functions in efferocytosis. Inhibition or deficiency of Mertk led to a release from T cell regulation characterized by enhanced T cell arrest in pre-diabetic islets and at the tumor site. This T cell arrest was accompanied by increased T cell-antigen presenting cell interactions as well as increased antigen experience and effector function by T cells in the islets. Notably, the effect of Mertk inhibition on T cell regulation was only seen at the disease site in the islets, not in draining lymph nodes. Inhibition of Mertk-dependent T cell regulation culminated in the rapid acceleration of autoimmune pathology and disease. In human islets, the number of Mertk-expressing cells were increased in remaining insulin-containing islets from type 1 diabetic patients, suggesting that they might have a protective role in human disease. These data indicate that Mertk signaling in mononuclear phagocytes drives T cell regulation that functions specifically at the disease site in peripheral tissues through a mechanism that prevents T cell arrest and response to antigen.

Download Full-text

Treatment of type 1 diabetes with anti-T-cell agents: From T-cell depletion to T-cell regulation

Current Diabetes Reports ◽

10.1007/s11892-004-0081-x ◽

2004 ◽

Vol 4 (4) ◽

pp. 291-297 ◽

Cited By ~ 5

Author(s):

Mariela Glandt ◽

Kevan C. Herold

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cell Depletion ◽

Cell Regulation ◽

T Cell Depletion ◽

T Cell Regulation

Download Full-text

T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus

Acta Endocrinologica ◽

10.1530/eje.0.1410272 ◽

1999 ◽

pp. 272-278 ◽

Cited By ~ 12

Author(s):

F Dotta ◽

S Dionisi ◽

V Viglietta ◽

C Tiberti ◽

MC Matteoli ◽

...

Keyword(s):

Cell Proliferation ◽

Type 1 Diabetes ◽

T Cell ◽

T Lymphocyte ◽

Tyrosine Phosphatase ◽

T Cell Response ◽

T Cell Proliferation ◽

Diabetic Patients ◽

Hla Dr

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

Download Full-text

Neutrophil Cytosolic Factor 1 in Dendritic Cells Promotes Autoreactive CD8+ T Cell Activation via Cross-Presentation in Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2019.00952 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Chao Liu ◽

Robert L. Whitener ◽

Andrea Lin ◽

Yuan Xu ◽

Jing Chen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell ◽

Cross Presentation ◽

Cytosolic Factor

Download Full-text

Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant

Journal of Autoimmunity ◽

10.1016/j.jaut.2008.01.001 ◽

2008 ◽

Vol 31 (1) ◽

pp. 13-21 ◽

Cited By ~ 51

Author(s):

Johanna Aarnisalo ◽

Andras Treszl ◽

Peter Svec ◽

Jane Marttila ◽

Viveka Öling ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell

Download Full-text

Establishment of T cell lines to bovine beta-casein and beta-casein-derived epitopes in patients with type 1 diabetes

Journal of Endocrinology ◽

10.1677/joe.0.1760143 ◽

2003 ◽

Vol 176 (1) ◽

pp. 143-150 ◽

Cited By ~ 14

Author(s):

L Monetini ◽

F Barone ◽

L Stefanini ◽

A Petrone ◽

T Walk ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Beta Cell ◽

Cell Line ◽

Cell Lines ◽

Diabetic Patients ◽

Beta Casein ◽

T Cell Lines ◽

Human Insulinoma

Enhanced cellular immune response to bovine beta-casein has been reported in patients with type 1 diabetes. In this study we aimed to establish beta-casein-specific T cell lines from newly diagnosed type 1 diabetic patients and to characterise these cell lines in terms of phenotype and epitope specificity. Furthermore, since sequence homologies exist between beta-casein and putative beta-cell autoantigens, reactivity to the latter was also investigated. T cell lines were generated from the peripheral blood of nine recent onset type 1 diabetic patients with different HLA-DQ and -DR genotypes, after stimulation with antigen pulsed autologous irradiated antigen presenting cells (APCs) and recombinant human interleukin-2 (rhIL-2). T cell line reactivity was evaluated in response to bovine beta-casein, to 18 overlapping peptides encompassing the whole sequence of beta-casein and to beta-cell antigens, including the human insulinoma cell line, CM, and a peptide from the beta-cell glucose transporter, GLUT-2. T cell lines specific to beta-casein could not be isolated from HLA-matched and -unmatched control subjects. beta-Casein T cell lines reacted to different sequences of the protein, however a higher frequency of T cell reactivity was observed towards the C-terminal portion (peptides B05-14, and B05-17 in 5/9 and 4/9 T cell lines respectively). Furthermore, we found that 1 out of 9 beta-casein-specific T cell lines reacted also to the homologous peptide from GLUT-2, and that 3 out of 4 of tested cell lines reacted also to extracts of the human insulinoma cell line, CM. We conclude that T cell lines specific to bovine beta-casein can be isolated from the peripheral blood of patients with type 1 diabetes; these cell lines react with multiple and different sequences of the protein particularly towards the C-terminal portion. In addition, reactivity of beta-casein T cell lines to human insulinoma extracts and GLUT-2 peptide was detected, suggesting that the potential cross-reactivity with beta-cell antigens deserves further investigation.

Download Full-text