CD2 expressing innate lymphoid and T cells are critical effectors of immunopathogenesis in hidradenitis suppurativa

• 成果类型: Article
• 署名作者: Kashyap, Mahendra Pratap; Mishra, Bharat; Sinha, Rajesh; Jin, Lin; Gou, Yifei; Kumar, Nilesh; Goliwas, Kayla F.; Haque, Safiya; Deshane, Jessy; Berglund, Erik; Berglund, David; Elewski, Boni E.; Elmets, Craig A.; Athar, Mohammad; Mukhtar, M. Shahid; Raman, Chander
• 署名单位: University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; University of Alabama System; University of Alabama Birmingham; Karolinska Institutet; Karolinska Institutet; Karolinska Institutet; Uppsala University; Clemson University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15096
• DOI: 10.1073/pnas.2409274121
• 发表日期: 2024-11-26
• 关键词: nk cells; activation

摘要

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease with a poorly understood immunopathogenesis. Here, we report that HS lesional skin is characterized by the expansion of innate lymphocytes and T cells expressing CD2, an essential activation receptor and adhesion molecule. Lymphocytes expressing elevated CD2 predominated with unique spatial distribution throughout the epidermis and hypodermis in the HS lesion. CD2+ cells were mainly innate lymphocytes expressing the NK cell marker, CD56, and CD4+ T cells. Importantly, these CD2+ cells interacted with CD58 (LFA3) expressing epidermal keratinocytes and fibroblasts in the hypodermis. Granzyme A bright NKT cells (CD2+CD3+CD56bright) clustered with alpha- SMA expressing fibroblasts juxtaposed to epithelialized tunnels and fibrotic regions of the hypodermis. Whereas NK cells (CD2+CD56dim) were perforin+, granzymes A+ and B+, and enriched adjacent to hyperplastic follicular epidermis and tunnels of HS showing presence of apoptotic cells. The cytokines IL- 12, IL- 15, and IL- 18, which enhance NK cell maturation and function were significantly elevated in HS. Ex vivo HS skin explant cultures treated with CD2:CD58 interaction- blocking anti-CD2 monoclonal antibody attenuated secretion of inflammatory cytokines/chemokines and suppressed inflammatory gene signature. Additionally, CD2:CD58 blockade altered miRNAs involved in NK/ NKT differentiation and/or function. In summary, we show that a cellular network of heterogenous NKT and NK cell populations drives inflammation and is critical in the pathobiology of HS, including tunnel formation and fibrosis. Finally, CD2 blockade is a viable immunotherapeutic approach for the effective management of HS.