Tertiary lymphoid tissue with germinal centers and T follicular helper cells in immunologically privileged retinas of mice with chronic autoimmune uveitis

FARE Award Winner

Authors

• JL Kielczewski
• R Horai
• Y Jittayasothorn
• CC Chan
• RR Caspi

Abstract

We developed a spontaneous uveitis mouse model (R161H), which expresses a retina-specific T cell receptor for Interphotoreceptor Binding Protein, a uveitis target antigen. These transgenic mice develop spontaneous uveitis that resembles human disease with distinct retinal lesions that resemble tertiary lymphoid tissue (TLT). We determined whether the retinal lymphoid structures represent TLT. Mouse retinas underwent immunohistochemical analysis. Laser capture microdissection was used to isolate the retinal lesions and gene expression arrays were performed. Immunohistochemistry revealed that the retinal lesions stained for CD4+ T cells and B cells in well-defined zonal areas. The retinal lesions also stained positively for germinal center markers, PNA and GL-7, which are typically expressed in TLT. Laser captured microdissected samples of the retinal lesions showed upregulation of T follicular helper cell markers, most notably CXCR5 and its ligand CXCL13, which are also typically expressed in TLT. In addition, immunohistochemical analysis of the retinal lymphoid aggregates revealed presence of T follicular helper cells (co-stained for CXCR5+/CD4+). We detected evidence for antigen presentation to retina-specific T cells within the TLT by co-labeling for CD11c+, pZap70+, and CD4+ IRBP specific T cells. Likewise, CD138+/B220+ plasma cells were detected in the TLT, suggesting they are a source of autoantibody production. Lastly, we found that mice with progressive late stage retinal aggregates had reduced visual activity compared to mice lacking these retinal structures. Our findings suggest that the TLT are pathological sites where immune cells can accumulate to create an environment conducive to immune cell activation and autoantibody production.

Scientific Focus Area: Immunology

This page was last updated on Friday, March 26, 2021