Session Type: ACR Abstract Session
Session Time: 4:30PM-6:00PM
Background/Purpose: In IgG4-related disease (IgG4-RD), both activated B cells and CD4+ cytotoxic T lymphocytes (CD4+CTLs) expand clonally, accumulate in tissues, likely recognize distinct epitopes on the same protein antigens, and thus, work together to contribute to fibrosis. We have previously reported that CD4+CTLs synthesize IL-1β and TGF-β in disease tissues, indicating that they are reactivated at lesional sites by antigen presenting cells, possibly activated B cells. However, the effector subset of CD4+CTLs and the mechanism by which they contribute to fibrosis has not yet been determined.
Methods: We used multi-color flow cytometry to identify subsets of CD4+CTLs. CD4+CTL subsets were quantified in the blood of 48 IgG4-RD subjects at the time of active disease and correlated with clinical parameters. Twenty age-matched healthy donors and 19 non-fibrotic sarcoidosis patients were used as controls. We then examined the TCR clonal frequencies and transcriptional profiles comparing CD4+CTL subsets using Next Generation Sequencing. Finally, we used multi-color immunofluorescence to determine tissue infiltration by effector CD4+CTLs and explore the possibility that apoptosis contributes to fibrosis in IgG4-RD.
Results: Compared to other subsets, the CD28LowCD57Hi subset of CD4+CTLs accumulated to the greatest degree in the blood of IgG4-RD patients with the most severe clinical phenotype. The CD28LowCD57Hi subset of CD4+CTLs demonstrated marked clonal-expansion and had a transcriptional profile suggesting that these cells are poised for survival, metabolically active and activated through TCR engagement. In contrast, the CD28HiCD57Low subset of CD4+CTLs accounted for most CD4+CTLs in the blood of healthy individuals, were reduced in the blood of IgG4-RD patients and enriched for a regulatory transcriptional phenotype with FoxP3 upregulation. These subsets expressed differing chemokine receptors suggesting different tissue honing capacity. In the diseased tissues, CD4+CTLs and B cells make cell-cell contact suggesting that B cells either present antigens to CD4+CTLs or secrete activating cytokines. Additionally, we demonstrated increased activated caspase-3 in disease tissues, particularly, in cells of mesenchymal origin.
Conclusion: The CD28LowCD57Hi subset of CD4+CTLs is clonally-expanded in IgG4-RD and correlates with disease severity. This subset is metabolically active, TCR-activated and infiltrates diseased tissues, suggesting an effector phenotype. The physical contact of B cells and CD4+CTLs in IgG4-RD tissues, along with the observed increase in caspase activation, suggests a possible mechanism of fibrosis in IgG4-RD such that CD4+CTLs, activated by antigen-presenting B cells, may cause apoptotic death of vimentin positive stromal cells. The ensuing cytokine secretion by activated CD4+CTLs and B cells might contribute to an over-exuberant tissue healing process, resulting in fibrosis. (Supported by NIH U19 AI 110495 and UM1 AI144295)
To cite this abstract in AMA style:Perugino C, Kaneko N, Kers J, Maehara T, Mattoo H, Liu H, Mahajan V, Ghebremichael M, Allard-Chamard H, Tuncay Y, Della Torre E, Wallace Z, Liang L, Montesi S, Stone J, Pillai S. Clonal Expansion of a Specific Subset of Cytotoxic CD4+T Cells and Tissue Apoptosis in Patients with IgG4-related Disease [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/clonal-expansion-of-a-specific-subset-of-cytotoxic-cd4t-cells-and-tissue-apoptosis-in-patients-with-igg4-related-disease/. Accessed November 22, 2019.
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