Single-immunocyte transcriptomics reveal the role of natural killer cell-dependent exogenous antigen presentation in ankylosing spondylitis severity.

Abstract

Ankylosing spondylitis (AS) is an autoimmune disease that can cause severe deformities, and the immunological patterns associated with its onset and progression remain poorly understood. Here, after recruiting healthy donors and patients in different stages, we performed single-cell RNA sequencing for peripheral blood mononuclear cells to investigate the cytotaxonomic and immunological hallmarks associated with AS onset, aggravation and remission and explore the intrinsic laws causing AS lesions. The results showed that innate antibacterial defense functions were generally enhanced in most cell types at disease onset and were negatively associated with AS severity. The abundance and exogenous antigen presentation scores of the natural killer (NK) cell subset characterized as antigen-presenting cells (APC-NK) increased during disease aggravation but decreased during remission. Generally, APC-NK abundance and their presentation scores were negatively correlated with innate defense scores for multiple cell types. CD4effector T cell abundance and cytotoxicity, as well as the enhancement of CD4T cell responses by HLA-DRB1NK cells (similar to APC-NK), were associated with AS severity. The implantation of HLA-DRB1NK cells accelerated AS-like alterations in SKG modeling mice with curdlan induction; this was blocked with CD4T cell exhaustion. NK cell exhaustion improved the phenotypes of AS-like mice. HLA-DPB1/DPA1 in APC-NK participated in AS aggravation by mediating antigen presentation targeting CD4T cells. Overall, innate defense antigen presentation coupling drives AS lesions and different outcomes. Furthermore, the trade-off between innate defense and NK-dependent exogenous antigen presentation results in CD4T cell activation or inactivation, thereby contributing to AS aggravation or remission; this reveals that APC-NK is a crucial factor causing ankylosing deformities.