Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II
Background and Aims: Refractory celiac disease type II (RCDII) is characterized by a clonally expanded aberrant cell population in the small intestine. The role of other tissue-resident immune subsets in RCDII is unknown. Here, we characterized CD8 and CD4 T cells in RCDII duodenum at the single-cel...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Gastro Hep Advances |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772572324001390 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832595723437211648 |
|---|---|
| author | Tessa Dieckman Mette Schreurs Ciska Lindelauf Ahmed Mahfouz Caroline R. Meijer Louise Pigeaud Vincent van Unen Gerd Bouma Frits Koning |
| author_facet | Tessa Dieckman Mette Schreurs Ciska Lindelauf Ahmed Mahfouz Caroline R. Meijer Louise Pigeaud Vincent van Unen Gerd Bouma Frits Koning |
| author_sort | Tessa Dieckman |
| collection | DOAJ |
| description | Background and Aims: Refractory celiac disease type II (RCDII) is characterized by a clonally expanded aberrant cell population in the small intestine. The role of other tissue-resident immune subsets in RCDII is unknown. Here, we characterized CD8 and CD4 T cells in RCDII duodenum at the single-cell level and in situ. Methods: We applied mass cytometry on CD45+ duodenal cells derived from intestinal biopsies (n = 23) and blood samples (n = 20) from RCDII patients and controls. Additionally, we analyzed intestinal biopsies from celiac disease (n = 11) and RCDI (n = 2) patients. We performed single-cell RNA-sequencing on CD45+ duodenal cells derived from a RCDII patient, immunofluorescence staining for in situ analysis and flow cytometry for phenotyping of RCDII aberrant and CD8 T cells. Results: Compared to healthy controls, we observed that CD27+PD-1+ memory CD8αβ cells and CD4 T regulatories (Tregs) were more abundant in RCDII duodenum (CD8 ∗∗0.0029; CD4 ∗∗∗0.0001). The CD27+PD-1+ memory CD8αβ cells expressed the tissue-resident marker CD69, immunoregulatory markers (TIGIT, HAVCR2, TNFRSF9), NKG2A, were enriched for activated pathways and displayed cytotoxic gene signatures (NKG7, PRF1, GZMA). The absence of CD103 accords with their localization in the lamina propria as determined by in situ analysis. The CD25+FoxP3+CD27+CD127dim/- CD4 Tregs expressed IL1R2 and IL32 and costimulatory molecules (TNFSRS4, ICOS and TNFRSF18) and resided in the lamina propria as well. Flow cytometry confirmed the presence of the inhibitory receptor NKG2A on expanded duodenal CD8 T cells and HLA-E, the ligand for NKG2A, on expanded aberrant cells. Conclusion: RCDII is characterized by the simultaneous presence of an activated CD27+PD-1+ memory CD8αβ T cell subset and CD4 Tregs, suggesting that checkpoint blockade with anti-NKG2A/PD-1 and/or anticytotoxic T lymphocyte antigen 4 may be an attractive treatment option. |
| format | Article |
| id | doaj-art-f2b01321167a463090eb8cb2b1b277b2 |
| institution | Kabale University |
| issn | 2772-5723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Gastro Hep Advances |
| spelling | doaj-art-f2b01321167a463090eb8cb2b1b277b22025-01-18T05:05:34ZengElsevierGastro Hep Advances2772-57232025-01-0141100545Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type IITessa Dieckman0Mette Schreurs1Ciska Lindelauf2Ahmed Mahfouz3Caroline R. Meijer4Louise Pigeaud5Vincent van Unen6Gerd Bouma7Frits Koning8Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, the NetherlandsDelft Bioinformatics Lab, Delft University of Technology, Delft, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Paediatrics, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Paediatrics, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, the Netherlands; Correspondence: Address correspondence to: Frits Koning, PhD, Department of Immunology, Leiden University Medical Center, Building 1, Albinusdreef 2, 2223 ZA, Leiden, the Netherlands.Background and Aims: Refractory celiac disease type II (RCDII) is characterized by a clonally expanded aberrant cell population in the small intestine. The role of other tissue-resident immune subsets in RCDII is unknown. Here, we characterized CD8 and CD4 T cells in RCDII duodenum at the single-cell level and in situ. Methods: We applied mass cytometry on CD45+ duodenal cells derived from intestinal biopsies (n = 23) and blood samples (n = 20) from RCDII patients and controls. Additionally, we analyzed intestinal biopsies from celiac disease (n = 11) and RCDI (n = 2) patients. We performed single-cell RNA-sequencing on CD45+ duodenal cells derived from a RCDII patient, immunofluorescence staining for in situ analysis and flow cytometry for phenotyping of RCDII aberrant and CD8 T cells. Results: Compared to healthy controls, we observed that CD27+PD-1+ memory CD8αβ cells and CD4 T regulatories (Tregs) were more abundant in RCDII duodenum (CD8 ∗∗0.0029; CD4 ∗∗∗0.0001). The CD27+PD-1+ memory CD8αβ cells expressed the tissue-resident marker CD69, immunoregulatory markers (TIGIT, HAVCR2, TNFRSF9), NKG2A, were enriched for activated pathways and displayed cytotoxic gene signatures (NKG7, PRF1, GZMA). The absence of CD103 accords with their localization in the lamina propria as determined by in situ analysis. The CD25+FoxP3+CD27+CD127dim/- CD4 Tregs expressed IL1R2 and IL32 and costimulatory molecules (TNFSRS4, ICOS and TNFRSF18) and resided in the lamina propria as well. Flow cytometry confirmed the presence of the inhibitory receptor NKG2A on expanded duodenal CD8 T cells and HLA-E, the ligand for NKG2A, on expanded aberrant cells. Conclusion: RCDII is characterized by the simultaneous presence of an activated CD27+PD-1+ memory CD8αβ T cell subset and CD4 Tregs, suggesting that checkpoint blockade with anti-NKG2A/PD-1 and/or anticytotoxic T lymphocyte antigen 4 may be an attractive treatment option.http://www.sciencedirect.com/science/article/pii/S2772572324001390CoeliacGluten enteropathyEnteropathy-associated T cell lymphomaSingle-cell analysis |
| spellingShingle | Tessa Dieckman Mette Schreurs Ciska Lindelauf Ahmed Mahfouz Caroline R. Meijer Louise Pigeaud Vincent van Unen Gerd Bouma Frits Koning Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II Gastro Hep Advances Coeliac Gluten enteropathy Enteropathy-associated T cell lymphoma Single-cell analysis |
| title | Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II |
| title_full | Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II |
| title_fullStr | Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II |
| title_full_unstemmed | Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II |
| title_short | Activated CD27+PD-1+ CD8 T Cells and CD4 T Regulatory Cells Dominate the Tumor Microenvironment in Refractory Celiac Disease Type II |
| title_sort | activated cd27 pd 1 cd8 t cells and cd4 t regulatory cells dominate the tumor microenvironment in refractory celiac disease type ii |
| topic | Coeliac Gluten enteropathy Enteropathy-associated T cell lymphoma Single-cell analysis |
| url | http://www.sciencedirect.com/science/article/pii/S2772572324001390 |
| work_keys_str_mv | AT tessadieckman activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT metteschreurs activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT ciskalindelauf activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT ahmedmahfouz activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT carolinermeijer activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT louisepigeaud activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT vincentvanunen activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT gerdbouma activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii AT fritskoning activatedcd27pd1cd8tcellsandcd4tregulatorycellsdominatethetumormicroenvironmentinrefractoryceliacdiseasetypeii |