Abstract
ObjectivesMultiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh populations and their association with disease activity in IgG4-RD.MethodsTIGIT expression in peripheral CD4+T cell subsets was comprehensively analyzed by multi-color flow cytometry. Single cell mapping was performed by t-SNE method, and IL-21 production was compared in TIGIT+ and TIGIT-T cells. The effect of OX40 signal on cytokine expression was analyzed by RNA-sequencing. Clinical significance of TIGIT+ and TIGIT- peripheral T cells was analyzed in active patients with IgG4-RD, both at baseline and after 12 weeks of glucocorticoid treatment.ResultsUnbiased single cell mapping revealed two high IL-21-producing peripheral T cell populations; TIGIT+ Tfh and TIGIT-T helper cells. OX40 signal was associated with high IL-21 production in TIGIT+ Tfh and TIGIT-T helper cells. IL-21 production in Tfh cells correlated with the proportion of TIGIT+ cells in Tfh cells, serum IgG4 level, and scores of disease activity. Furthermore, the skewing toward peripheral TIGIT+ Tfh cells, particularly TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD.ConclusionsOX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD.
Highlights
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by storiform fibrosis, IgG4+ plasma cell infiltration, and elevated levels of serum IgG4 [1,2,3,4]
The skewing toward peripheral TIGIT+ T follicular helper (Tfh) cells, TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD
OX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD
Summary
IgG4-related disease (IgG4-RD) is a fibro-inflammatory disease characterized by storiform fibrosis, IgG4+ plasma cell infiltration, and elevated levels of serum IgG4 [1,2,3,4]. Mounting evidence has revealed that T follicular helper (Tfh) cells, which induce hyperplastic tertiary lymphoid organ formation, IgG4 class-switching, and plasma cell differentiation, are involved in the pathogenesis of IgG4-RD [5,6,7,8,9,10,11,12,13,14,15]. CD4+ cytotoxic T cells cause tissue damage and fibrosis [16,17,18,19]. IL-21 is produced by CD4+ T cells, with high production by Tfh cells, and plays a key role in B cell differentiation and maturation and in enhancing the activity and survival of CD4+ cytotoxic T cells [21, 22]. IL-21-producing Tfh cells may be a key immune cell subset involved in the pathogenesis of IgG4-RD
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