Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes
Variation in the preservation of β cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3–Ig) and demonstrated C-peptide preservation in approximately 30% of new-onse...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.167881 |
| _version_ | 1797634263556816896 |
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| author | Elisa Balmas Janice Chen Alex K. Hu Hannah A. DeBerg Mario G. Rosasco Vivian H. Gersuk Elisavet Serti Cate Speake Carla J. Greenbaum Gerald T. Nepom Peter S. Linsley Karen Cerosaletti |
| author_facet | Elisa Balmas Janice Chen Alex K. Hu Hannah A. DeBerg Mario G. Rosasco Vivian H. Gersuk Elisavet Serti Cate Speake Carla J. Greenbaum Gerald T. Nepom Peter S. Linsley Karen Cerosaletti |
| author_sort | Elisa Balmas |
| collection | DOAJ |
| description | Variation in the preservation of β cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3–Ig) and demonstrated C-peptide preservation in approximately 30% of new-onset T1D individuals. We analyzed islet antigen–reactive (IAR) CD4+ T cells in PBMC samples collected prior to treatment from alefacept- and placebo-treated individuals using flow cytometry and single-cell RNA sequencing. IAR CD4+ T cells at baseline had heterogeneous phenotypes. Transcript profiles formed phenotypic clusters of cells along a trajectory based on increasing maturation and activation, and T cell receptor (TCR) chains showed clonal expansion. Notably, the frequency of IAR CD4+ T cells with a memory phenotype and a unique transcript profile (cluster 3) were inversely correlated with C-peptide preservation in alefacept-treated, but not placebo-treated, individuals. Cluster 3 cells had a proinflammatory phenotype characterized by expression of the transcription factor BHLHE40 and the cytokines GM-CSF and TNF-α, and shared TCR chains with effector memory–like clusters. Our results suggest IAR CD4+ T cells as a potential baseline biomarker of response to therapies targeting the CD2 pathway and warrant investigation for other T cell–related therapies. |
| first_indexed | 2024-03-11T12:06:14Z |
| format | Article |
| id | doaj.art-fc5124fb6eab4bc1a3e7082177f0b113 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:14Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-fc5124fb6eab4bc1a3e7082177f0b1132023-11-07T16:26:23ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01821Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetesElisa BalmasJanice ChenAlex K. HuHannah A. DeBergMario G. RosascoVivian H. GersukElisavet SertiCate SpeakeCarla J. GreenbaumGerald T. NepomPeter S. LinsleyKaren CerosalettiVariation in the preservation of β cell function in clinical trials in type 1 diabetes (T1D) has emphasized the need to define biomarkers to predict treatment response. The T1DAL trial targeted T cells with alefacept (LFA-3–Ig) and demonstrated C-peptide preservation in approximately 30% of new-onset T1D individuals. We analyzed islet antigen–reactive (IAR) CD4+ T cells in PBMC samples collected prior to treatment from alefacept- and placebo-treated individuals using flow cytometry and single-cell RNA sequencing. IAR CD4+ T cells at baseline had heterogeneous phenotypes. Transcript profiles formed phenotypic clusters of cells along a trajectory based on increasing maturation and activation, and T cell receptor (TCR) chains showed clonal expansion. Notably, the frequency of IAR CD4+ T cells with a memory phenotype and a unique transcript profile (cluster 3) were inversely correlated with C-peptide preservation in alefacept-treated, but not placebo-treated, individuals. Cluster 3 cells had a proinflammatory phenotype characterized by expression of the transcription factor BHLHE40 and the cytokines GM-CSF and TNF-α, and shared TCR chains with effector memory–like clusters. Our results suggest IAR CD4+ T cells as a potential baseline biomarker of response to therapies targeting the CD2 pathway and warrant investigation for other T cell–related therapies.https://doi.org/10.1172/jci.insight.167881Autoimmunity |
| spellingShingle | Elisa Balmas Janice Chen Alex K. Hu Hannah A. DeBerg Mario G. Rosasco Vivian H. Gersuk Elisavet Serti Cate Speake Carla J. Greenbaum Gerald T. Nepom Peter S. Linsley Karen Cerosaletti Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes JCI Insight Autoimmunity |
| title | Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes |
| title_full | Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes |
| title_fullStr | Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes |
| title_full_unstemmed | Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes |
| title_short | Islet-autoreactive CD4+ T cells are linked with response to alefacept in type 1 diabetes |
| title_sort | islet autoreactive cd4 t cells are linked with response to alefacept in type 1 diabetes |
| topic | Autoimmunity |
| url | https://doi.org/10.1172/jci.insight.167881 |
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