Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity

Harshi Weerakoon; Jasmin Straube; Katie Lineburg; Leanne Cooper; Steven Lane; Corey Smith; Saleh Alabbas; Jakob Begun; John J Miles; Michelle M Hill; Ailin Lepletier

doi:10.1002/cti2.1334

Expression of CD49f defines subsets of human regulatory T cells with divergent transcriptional landscape and function that correlate with ulcerative colitis disease activity

Clin Transl Immunology. 2021 Sep 6;10(9):e1334. doi: 10.1002/cti2.1334. eCollection 2021.

Authors

Harshi Weerakoon^{1

2

3}, Jasmin Straube⁴, Katie Lineburg⁵, Leanne Cooper⁴, Steven Lane^{4

6}, Corey Smith⁵, Saleh Alabbas⁷, Jakob Begun^{6

7

8}, John J Miles^{9

10}, Michelle M Hill^{1

11}, Ailin Lepletier^{9

12}

Affiliations

¹ Precision and Systems Biomedicine Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
² School of Biomedical Sciences The University of Queensland Brisbane QLD Australia.
³ Department of Biochemistry Faculty of Medicine and Allied Sciences Rajarata University of Sri Lanka Saliyapura Sri Lanka.
⁴ Gordon and Jessie Gilmour Leukaemia Research Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
⁵ Translational and Human Immunology Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
⁶ School of Medicine University of Queensland Brisbane QLD Australia.
⁷ Inflammatory Bowel Diseases Research Group Mater Research Institute University of Queensland Brisbane QLD Australia.
⁸ Mater Hospital Brisbane Brisbane QLD Australia.
⁹ Human Immunity Laboratory QIMR Berghofer Medical Research Institute Herston QLD Australia.
¹⁰ Centre for Biodiscovery and Molecular Development of Therapeutics James Cook University Cairns QLD Australia.
¹¹ Centre for Clinical Research Faculty of Medicine The University of Queensland Brisbane QLD Australia.
¹² Laboratory of Vaccines for the Developing World Institute for Glycomics Southport QLD Australia.

Abstract

Objective: Adoptive regulatory T cell (Treg) therapy is being trialled for the treatment of different autoimmune disorders, including inflammatory bowel diseases (IBD). In-depth understanding of the biological variability of Treg in the human blood may be required to improve IBD immune monitoring and treatment strategies.

Methods: Through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-sequencing data analysis and functional assays on Treg enriched from the blood of ulcerative colitis (UC) patients and healthy controls, we investigated the association between CD49f expression, Treg phenotype and function, and UC disease activity.

Results: High-dimensional analysis and filtering defined two distinct subsets of human Treg based on the presence or absence of CD49f with divergent transcriptional landscape and functional activities. CD49f negative (CD49f^-) Treg are enriched for functional Treg markers and present significantly increased suppressive capacity. In contrast, CD49f^high Treg display a pro-inflammatory Th17-like phenotype and accumulate in the blood of patients with UC. Dysregulation on CD49f Treg subsets in patients with UC correlate with disease activity.

Conclusion: Overall, our findings uncover the importance of CD49f expression on Treg in physiological immunity and in pathological autoimmunity.

Keywords: CD49f (integrin alpha 6); adaptative immunity; cellular immunity; interleukin‐17A (IL‐17A); regulatory T cells; ulcerative colitis.