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. 2022 Jul 28:13:937109.
doi: 10.3389/fendo.2022.937109. eCollection 2022.

Altered expression of Tim family molecules and an imbalanced ratio of Tim-3 to Tim-1 expression in patients with type 1 diabetes

Yikai Liu  1 , Zhiying Chen  1 , Yang Xiao  1 , Hongzhi Chen  1 , Zhiguang Zhou  1
Affiliations

Altered expression of Tim family molecules and an imbalanced ratio of Tim-3 to Tim-1 expression in patients with type 1 diabetes

Yikai Liu et al. Front Endocrinol (Lausanne). .

Abstract

Background: T-cell immunoglobulin and mucin domain (Tim) proteins are immunomodulatory molecules that play key roles in the regulation of T-cell activation. Published studies have reported that Tim molecules are involved in the pathogenesis of certain autoimmune diseases. Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate the destruction of islet β cells. However, the expression of Tim molecules in T1D remains unclear. In this study, we measured the expression of Tim family molecules as well as T-cell subset-specific transcription factors in T1D patients, and we explored the possible involvement of Tim molecules in the pathogenesis of T1D.

Methods: Ninety T1D patients, Thirty-six type 2 diabetes (T2D) patients and forty healthy controls (HCs) were recruited for this study. Peripheral blood mononuclear cells (PBMCs) were isolated, RNA was extracted from the PBMCs and reverse transcribed into cDNA, and gene expression patterns were analysed by RT-qPCR. The expression of Tim molecules in different T-cell subsets was analysed by flow cytometry.

Results: Compared with that in HCs, the mRNA expression of Tim-1 and RORC was increased in T1D patients (P=0.0355 and P=0.0423, respectively), while the expression of Tim-3 was decreased (P=0.0013). In addition, compared with HCs, the ratio of Tim-3 to Tim-1 expression in diabetic patients was decreased (P<0.0001 for T1D and P=0.0387 for T2D). The ratios of T-Bet to GATA3 expression and RORC to FOXP3 expression were higher in T1D patients than in HCs (P=0.0042 and P=0.0066, respectively). Furthermore, the T1D patients with defective islet function had more significant imbalances in the Tim-3/Tim-1 and RORC/FOXP3 ratios (P<0.0001, and P=0.001, respectively). Moreover, Both Tim-3 expression in CD4+ T cells and the Tim-3 to Tim-1 ratio were elevated in T1D in the remission phase compared to T1D.

Conclusion: Our study revealed altered expression of Tim molecules in T1D patients. The imbalanced ratios of Tim-3/Tim-1 expression were more pronounced in T1D patients with defective islet function. However, alterations in Tim molecule expression are mitigated in T1D in the remission phase. All these findings suggest that Tim family molecules may be involved in the pathogenesis of T1D.

Keywords: T cell subset-specific transcription factors; Tim-1; Tim-3; Tim-4; type 1 diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The mRNA expression levels among T1D patients (n=40), T2D patients (n=36) and HCs (n=40) as quantified by RT–qPCR. (A) Tims mRNA expression in PBMCs from T1D patients, T2D patients and HCs. (B) T-cell subset-specific transcription factor mRNA expression in PBMCs from T1D patients, T2D patients and HCs. The error bars represent the standard deviation of the mean. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.
Figure 2
Figure 2
The ratios of Tim molecules and T-cell subset-specific transcription factor expression in T1D patients (n=40), T2D patients (n=36) and HCs (n=40). (A) The ratio of Tim-3 to Tim-1 expression in T1D patients, T2D patients and HCs. (B) The ratio of T-Bet to GATA3 expression in T1D patients, T2D patients and HCs. (C) The ratio of RORC to POXP3 expression in T1D patients, T2D patients and HCs. The error bars represent the standard deviation of the mean. *P<0.05; **P<0.01; ****P<0.0001.
Figure 3
Figure 3
The ratios of Tim molecules and T-cell subset-specific transcription factor expression in the T1D subgroups (n=40) and HCs (n=40). (A) The ratio of Tim-3 to Tim-1 in different T1D subgroups and the HC group. (B) The ratio of T-Bet to GATA3 in different T1D patient subgroups and the HC group. (C) The ratio of RORC to POXP3 in different T1D subgroups and the HC group. Error bars represent the standard deviation of the mean. *P<0.05; ***P<0.001; ****P<0.0001.
Figure 4
Figure 4
The expression of Tim-1 and Tim-3 in different T-cell subsets from T1D patients. (A) Representative plots showing the expression of Tim-1 and Tim-3 in different T-cell subsets. (B) The expression of Tim-1 on CD4+ and CD8+ T cells in T1D patients. (C) The expression of Tim-3 in CD4+ and CD8+ T cells in T1D patients. ns, no statistical difference; ***P<0.001.
Figure 5
Figure 5
The Tim-1 and Tim-3 expression in T-cell subsets from T1D and T1D in the remission phase. (A) Alterations in the expression of Tim-1+ CD4+ T cells from T1D in the remission phase compared with T1D. (B) Alterations in the expression of Tim-3+ CD4+ T cells from T1D in the remission phase compared with T1D. (C) Alterations in the expression of Tim-1+ CD8+ T cells from T1D in the remission phase compared with T1D. (D) Alterations in the expression of Tim-3+ CD8+ T cells from T1D in the remission phase compared with T1D. ns, no statistical difference; *P<0.05.
Figure 6
Figure 6
The ratio of Tim-3 to Tim-1 in different T-cell subsets form T1D and T1D in the remission phase. (A) The ratio of Tim-3 to Tim-1 in CD4+ T cells from T1D and T1D in the remission phase. (B) The ratio of Tim-3 to Tim-1 in CD8+ T cells from T1D and T1D in the remission phase. *P<0.05.;**P<0.01.
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