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Phenotype-Based Isolation of Antigen-Specific CD4+ T Cells in Autoimmunity: A Study of Celiac Disease
Asbjørn Christophersen1,2,3, Shiva Dahal-Koirala1,2, Markéta Chlubnová1,2
1KG Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, 0372, Norway.
Insights
Phenotypic sorting effectively isolates gluten-reactive CD4+ T cells in celiac disease (CeD). This method identifies disease-driving T cells, offering a new approach for autoimmune condition research.
Area of Science:
- Immunology
- Autoimmunity
- T-cell biology
Background:
- Celiac disease (CeD) involves pathogenic CD4+ T cells recognizing gluten epitopes.
- Distinct T-cell phenotypes are implicated in CeD and other autoimmune diseases.
- The specificity of these phenotypically distinct T cells remains largely unknown.
Purpose of the Study:
- To determine if sorting T cells by a distinct phenotype (Tphe cells) can isolate gluten-reactive cells in CeD.
- To benchmark this phenotypic sorting method against traditional tetramer-based isolation (Ttet cells).
Main Methods:
- Gut biopsies from 12 untreated CeD patients were used.
- T cells were sorted into Ttet+/Tphe+, Ttet-/Tphe+, and Ttet-/Tphe- groups.
- Single-cell TCR sequencing and T-cell clone (TCC) generation were performed.
- Generated TCCs were tested for reactivity against deamidated gluten.
Main Results:
- Gluten reactivity was found in 91.2% of Ttet+/Tphe+ TCCs and 65.3% of Ttet-/Tphe+ TCCs.
- No gluten reactivity was observed in Ttet-/Tphe- TCCs.
- TCR sequencing indicated clonal expansion and shared sequences among patients, suggesting antigen-driven responses.
Conclusions:
- Phenotypic sorting alone can isolate antigen-specific CD4+ T cells in CeD.
- This approach provides a potential method for characterizing disease-driving CD4+ T cells in autoimmune conditions.
- The findings open new avenues for understanding T-cell roles in autoimmunity.
Abstract:
The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease-associated HLA-DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten-reactive cells in CeD is tested. The method's efficiency is benchmarked by parallel isolation of gluten-reactive T cells (Ttet cells), using HLA-DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA-DQ2.5+ CeD patients, Ttet+ /Tphe+ , Ttet- /Tphe+ , and Ttet- /Tphe- cells are sorted for single-cell T-cell receptor (TCR)-sequencing (n = 8) and T-cell clone (TCC)-generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten-reactivity is observed in 91.2% of Ttet+ /Tphe+ TCCs, 65.3% of Ttet- /Tphe+ TCCs and 0% of Ttet- /Tphe- TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen-driven responses. The feasibility to isolate antigen-specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease-driving CD4+ T cells in autoimmune conditions.
