Immunoregulatory soluble CTLA-4 modifies effector T cell responses in systemic lupus erythematosus

Lekh N. Dahal, Neil Basu, Hazem Youssef, Rahul C. Khanolkar, Robert N. Barker, Lars P. Erwig, Frank J. Ward

Research output: Contribution to journalArticle

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Abstract

Background
The inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus (SLE).

Methods
The cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.

Results
We identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-γ) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.

Conclusion
The results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.
Original languageEnglish
Article number180
Pages (from-to)1-11
Number of pages11
JournalArthritis Research & Therapy
Volume18
DOIs
Publication statusPublished - 4 Aug 2016

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Systemic Lupus Erythematosus
Autoantigens
Blood Cells
Interleukin-17
T-Lymphocytes
Peptides
Tissue Donors
Interleukin-10
Cytokines
Cell Culture Techniques
Immunity
Healthy Volunteers
Small Nuclear Ribonucleoproteins
Antigens
Autoimmunity
Histones
Autoimmune Diseases
Protein Isoforms
Enzyme-Linked Immunosorbent Assay
Monoclonal Antibodies

Keywords

  • Soluble CTLA-4
  • Systemic lupus erythematosus
  • Immune regulation

Cite this

Immunoregulatory soluble CTLA-4 modifies effector T cell responses in systemic lupus erythematosus. / Dahal, Lekh N.; Basu, Neil; Youssef, Hazem; Khanolkar, Rahul C.; Barker, Robert N.; Erwig, Lars P.; Ward, Frank J.

In: Arthritis Research & Therapy, Vol. 18, 180, 04.08.2016, p. 1-11.

Research output: Contribution to journalArticle

Dahal, Lekh N. ; Basu, Neil ; Youssef, Hazem ; Khanolkar, Rahul C. ; Barker, Robert N. ; Erwig, Lars P. ; Ward, Frank J. / Immunoregulatory soluble CTLA-4 modifies effector T cell responses in systemic lupus erythematosus. In: Arthritis Research & Therapy. 2016 ; Vol. 18. pp. 1-11.
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abstract = "BackgroundThe inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus (SLE).MethodsThe cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.ResultsWe identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-γ) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.ConclusionThe results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.",
keywords = "Soluble CTLA-4, Systemic lupus erythematosus, Immune regulation",
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note = "Acknowledgments This work was supported by Arthritis Research UK (Grant no. 19282). We are grateful to Dr. Nick Fluck for his invaluable support in recruiting patients for the study, and Mrs. Vivien Vaughan for her invaluable expertise in recruiting study participants and maintaining ethical documentation.",
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T1 - Immunoregulatory soluble CTLA-4 modifies effector T cell responses in systemic lupus erythematosus

AU - Dahal, Lekh N.

AU - Basu, Neil

AU - Youssef, Hazem

AU - Khanolkar, Rahul C.

AU - Barker, Robert N.

AU - Erwig, Lars P.

AU - Ward, Frank J.

N1 - Acknowledgments This work was supported by Arthritis Research UK (Grant no. 19282). We are grateful to Dr. Nick Fluck for his invaluable support in recruiting patients for the study, and Mrs. Vivien Vaughan for her invaluable expertise in recruiting study participants and maintaining ethical documentation.

PY - 2016/8/4

Y1 - 2016/8/4

N2 - BackgroundThe inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus (SLE).MethodsThe cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.ResultsWe identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-γ) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.ConclusionThe results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.

AB - BackgroundThe inhibitory CTLA-4 molecule is a crucial regulator of immune responses and a target for therapeutic intervention in both autoimmunity and cancer. In particular, CTLA-4 is important in controlling antigen-specific immunity, including responses to autoantigens associated with autoimmune disease. Here, we investigate cytokine responses to a range of lupus-associated autoantigens and assess whether the alternatively spliced isoform of CTLA-4, soluble CTLA-4 (sCTLA-4), contributes to immune regulation of autoantigen-specific immunity in systemic lupus erythematosus (SLE).MethodsThe cell culture supernatant production of sCTLA-4 as well as the cytokines IL-10, IFN-γ, and IL-17 from peripheral blood mononuclear cells (PBMC) from lupus patients and age- and sex-matched healthy volunteer donors were measured in response to previously identified histone and small nuclear ribonucleoprotein (snRNP) autoantigen-derived peptides (H391-105, H471-93, and U170K131-151) by ELISA. We also examined the functional contribution of sCTLA-4 to immune regulation in the context of these autoantigenic peptides following blockade of sCTLA-4 with a selective anti-sCTLA-4 monoclonal antibody, JMW-3B3.ResultsWe identified responses to autoantigenic peptides, which revealed qualitative differences in cytokine (IL-10, IL-17, and IFN-γ) profiles between SLE patients and healthy donors. PBMC from healthy donors responded to each of the lupus peptides by secreting IFN-γ and IL-17, but PBMC from SLE patients produced IL-10. Although we did not observe differences in the levels of serum or PBMC culture supernatant sCTLA-4 in either cohort, blockade of sCTLA-4 in PBMC cultures responding to antigen enhanced the cytokine profiles associated with each group.ConclusionThe results show that lupus autoantigen-derived peptides display varied immunogenicity in lupus versus healthy volunteer donors, while sCTLA-4 acts to regulate the T-cell activity independently of response profile.

KW - Soluble CTLA-4

KW - Systemic lupus erythematosus

KW - Immune regulation

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DO - 10.1186/s13075-016-1075-1

M3 - Article

VL - 18

SP - 1

EP - 11

JO - Arthritis Research & Therapy

JF - Arthritis Research & Therapy

SN - 1478-6354

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