Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease

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.

IL-21 enhances influenza vaccine responses in aged macaques with suppressed SIV infection

“…However, upon further phenotypic characterization of CD4 + Tcm, we observed significantly elevated ( P = 0.0061) frequencies of TIGIT-expressing CD4 + Tcm day 14 after B1 ( Figure 3A ), the same time point at which SIV + IL-21–treated animals had significantly improved influenza HAI titers compared with SIV + IL-21–untreated animals ( Figure 1E ). Interestingly, pTfh cells expressing TIGIT have recently been shown to exhibit strong B cell help functions and high levels of IL-21 production, and they have been shown to promote differentiation of plasmablasts and IgG production ( 26 , 39 ). Furthermore, we found that there was a trend ( P = 0.0727) of increased TIGIT expression on pTfh cells in IL-21–treated animals ( Figure 3D ), and influenza HAI titers day 14 after B1 correlated with both TIGIT + CD4 + Tcm ( r = 0.6808, P = 0.0120) ( Figure 3B ) and TIGIT + pTfh ( r = 0.7387, P = 0.0112) cells ( Figure 3E ).…”

Follicular Helper T Cells in the Immunopathogenesis of SARS-CoV-2 Infection

“…The specific transcription factor Bcl-6 is selectively expressed in Tfh cells but is highly expressed in CXCR5 hi CCR7 low/-Tfh cells in human and mouse GCs (34)(35)(36)(37). The IL-21 cytokine is highly and specifically secreted by Tfh cells, which promotes the proliferation of Tfh cells and helps B cell differentiation and antibody secretion, which is characteristic of Tfh cells (38)(39)(40)(41)(42). ICOS deficiency significantly reduces GC reactions and Tfh cells in mice and humans, which indicates that ICOS expressed in Tfh cells is essential for the differentiation and maintenance of Tfh cells, GC formation, B cell differentiation and antibody responses (43)(44)(45).…”

Immune Dysregulation in IgG4-Related Disease

“…T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), a co-inhibitory receptor discovered recently (84), was thought to be a novel Tfh marker. Akiyama et al (85) analyzed the expression of TIGIT in peripheral CD4 + T cell subsets and found that peripheral Tfh cells have higher expression of TIGIT than Th cells. They also observed that TIGIT + Tfh cells secretes more IL-21 than TIGIT -Tfh cells, which could be used to trace the progression of IgG4-RD.…”

“…Akiyama et al. ( 85 ) analyzed the expression of TIGIT in peripheral CD4 + T cell subsets and found that peripheral Tfh cells have higher expression of TIGIT than Th cells. They also observed that TIGIT + Tfh cells secretes more IL-21 than TIGIT - Tfh cells, which could be used to trace the progression of IgG4-RD.…”