Peptidase inhibitor 16 identifies a human regulatory T‐cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes

Abstract

CD4+ T‐cell subsets play a major role in the host response to infection, and a healthy immune system requires a fine balance between reactivity and tolerance. This balance is in part maintained by regulatory T cells (Treg), which promote tolerance, and loss of immune tolerance contributes to autoimmunity. As the T cells which drive immunity are diverse, identifying and understanding how these subsets function requires specific biomarkers. From a human CD4 Tconv/Treg cell genome wide analysis we identified peptidase inhibitor 16 (PI16) as a CD4 subset biomarker and we now show detailed analysis of its distribution, phenotype and links to Treg function in type 1 diabetes. To determine the clinical relevance of Pi16 Treg, we analysed PI16+ Treg cells from type 1 diabetes patient samples. We observed that FOXP3 expression levels declined with disease progression, suggesting loss of functional fitness in these Treg cells in Type 1 diabetes, and in particular the rate of loss of FOXP3 expression was greatest in the PI16+ve Treg. We propose that PI16 has utility as a biomarker of functional human Treg subsets and may be useful for tracking loss of immune function in vivo. The ability to stratify at risk patients so that tailored interventions can be applied would open the door to personalised medicine for Type 1 diabetes.

Adipose Tissue Properties in Tumor-Bearing Breasts

“…This association suggests that the secreted IL-8 originates at least partly from the mast cells compartment. (33); PI16 (peptidase inhibitor 16) which may be a biomarker of loss of immune tolerance through its expression in Treg cell subsets (34). The difference between the level of CD163 mRNA (2.2-fold upregulated in AdipTa+AdipTd) and the expression of the protein measured by IHC is noteworthy.…”

Molecular Insights Into Regulatory T-Cell Adaptation to Self, Environment, and Host Tissues: Plasticity or Loss of Function in Autoimmune Disease

“…Deeper interrogation of the function of Treg subsets is suggesting that differential expression of other cytokine/chemokine receptors on Treg may be useful for tracking Treg ex vivo . A growing number of other cell surface markers are found on specific Treg subsets, e.g., TIGIT ( 14 – 16 ), FcRL3 ( 17 ), GARP/LRRC32 ( 18 – 21 ), CD73 and CD39 ( 22 , 23 ), and, more recently, PI16 ( 24 ). The mechanism for TIGIT in establishing the suppressor function both directly and indirectly includes induction of tolerogenic dendritic cells ( 14 , 15 ), and coexpression with FcRL3 marks human memory Treg that express Helios and are highly suppressive ( 17 ).…”

Transcriptional re-programming in rat central nervous system two weeks after burn trauma: the impact of nephrilin treatment on the expression of oxidative stress-related genes

“…Peptidase Pi16 is a master regulator of T-cell subsets, a key function in the adaptive immune response in all tissues. 16 …”

“…Peptidase Pi16 is a master regulator of T-cell subsets, a key function in the adaptive immune response in all tissues. 16 Figure 1a shows the results obtained by RT-PCR of GFAP, CTGF, AQP4 and Pi16 genes using RNA extracted from CNS of scalded rats (with or without nephrilin treatment), with sham-treated rats as a control. The results show that burn injury causes significant increase in the expression of all four genes; nephrilin treatment significantly reduces those elevations.…”