Background/Purpose: IgG4-related disease (IgG4-RD) is a chronic immune-mediated fibrotic disease often causing multi-organ involvement. We have previously reported the association of SLAMF7+ CD4+ cytotoxic T lymphocytes (CD4+CTLs) with IgG-4RD including their dominance among the CD4 infiltrate in diseased tissues. In the context of chronic viral infections, such as HIV and CMV, CD4+CTL expansions have been observed to parallel those of CD8+CTLs. CD8+CTLs are additionally reported to be relevant to other autoimmune diseases such as Sjogren’s syndrome and Celiac disease. To date, no detailed examination of CD8+ CTLs has been reported in the setting of IgG4-RD.

Methods: We used multi-color flow cytometry to quantitate CD8+CTL subsets in the blood of 48 patients with IgG4-RD and explored correlations with disease severity, serum IgG4 levels and CD4+CTL expansions. We used 20 age-matched healthy individuals and 19 sarcoidosis patients without lung parenchymal fibrosis as controls. We performed TCR repertoire analysis and RNA sequencing using Next Generation Sequencing. Diseased tissues were interrogated for CD8+ T cell infiltrates using multi-color immunofluorescence.

Results: CD28^Low CD57^Hi CD8+CTLs are expanded in the blood of patients with IgG4-RD and correlate with disease severity, serum IgG4 level and expansion of effector CD4+CTLs. The majority of CD28^Low CD57^Hi CD8+CTLs in the blood have regained CD45RA expression (CD8+ TEMRA) and dominate over CD8+ TEM. In IgG4-RD, CD8+ TEM and CD8+ TEMRA cells are clonally restricted and highly connected to each other. In contrast to cells from healthy individuals, certain TCR V-beta genes are over-represented among CD28^Low CD57^Hi CD8+CTLs in IgG4-RD, and dominant V-beta genes are shared across different patients. In the context of IgG4-RD, the transcriptome of these cells suggests conditioning by an inflammatory microenvironment (IL-6, TNF-α, and IFN-γ signaling), heightened metabolic activity, increased cell proliferation, and an enhanced capacity to home to damaged tissues. SLAMF7+ CD8+CTLs infiltrate the involved tissues of IgG4-RD patients in high numbers, comparable to those of SLAMF7+ CD4+CTLs. Tissue infiltrating SLAMF7+ CD8+CTLs are composed of both CD8+ TEM and CD8+ TEMRA cells.

Conclusion: CD28^Low CD57^Hi CD8+CTLs are expanded in the blood of IgG4-RD and correlate with multiple parameters relevant to the mechanism of disease. In contrast to the same cell type from healthy individuals, these CD8+CTLs from IgG4-RD patients appear to be more active, proliferative and tissue-homing. The highly restricted TCR repertoire shows an over-represented V-beta gene usage that is shared across multiple IgG4-RD patients and differs from the    V-beta genes used by the the corresponding T cells in healthy individuals. The TCR V-beta usage suggests the possibility that the CD8+CTL responses are targeting shared class I restricted protein antigens across patients in a disease-specific manner. The accumulation of CD8+CTLs in disease lesions suggest that they may contribute  to the pathogenesis of IgG4-RD. (Supported by NIH U19 AI 110495 and UM1 AI144295)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd8-cytotoxic-t-lymphocytes-are-clonally-expanded-in-igg4-related-disease-and-home-to-affected-tissues/