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.

Diagnosis of disease is a complex process requiring the clinician to deduce, from a set of symptoms and observations, an underlying cause, to predict which of the several therapeutic options is most likely to be effective, and to monitor that effectiveness. Laboratory tests that identify infectious agents, abnormal cells or elements of the body's response to disease, that quantify or localise particular molecules, cells or organisms in body fluids or tissues can provide valuable information to help the clinician with the initial diagnosis, with differential diagnosis (when the symptoms are consistent with several alternative causes) and with selection and monitoring of therapy. Antibodies, because of their exquisite specificity, are particularly useful reagents in this context, and monoclonal antibodies generally show superior specificity compared with polyclonal mixtures of antibodies. Monoclonal antibodies are used widely in the diagnosis of disease, whether in the diagnostic laboratory, in the doctor's rooms or in the field. Key Concepts: Correct diagnosis is a prerequisite to appropriate treatment of disease. Antibodies make useful reagents for identifying infectious or other disease‐causing agents. Monoclonal antibodies are particularly specific and often provide the best diagnostic reagents. Antibodies can be used in a variety of assay formats, designed to answer different questions – presence or absence of a particular substance, amount present and localisation within tissues. The rapid identification of new or rare infectious agents is an important public health measure, to monitor and reduce the chances of epidemics (as we see every few years with a new threat from an influenza variant). Disease often results from imbalances or defects in normal physiological mechanisms, especially the immune system. Many diagnostic tests therefore analyse the components of normal physiological processes. Laboratory tests are useful after the initial diagnosis, to monitor the effects of therapy. Diagnostic tests are generally done in a specialised diagnostic laboratory, but it is often advantageous to perform tests at ‘point of care’ or at home.

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T helper (Th) cells play a major role in protecting the body against pathogens. Any imbalance in Th cell subsets could lead to autoimmune and inflammatory diseases. Peptidase inhibitor 16 (PI16), also known as prostate secretory protein of 94 amino acid - binding protein, was recently discovered to be expressed on memory regulatory T cells. This study investigates the expression and function of PI16 on Th cells. In healthy adults, 5-25% of CD4+ Th cells express PI16 with over 90% showing a memory phenotype. PI16+ Th cells have an increased expression of chemokine receptors CCR4 and CCR6 compared with PI16- Th cells. Transwell migration assays showed that more PI16+ Th cells migrated towards the CCR4 and CCR6 ligands (CCL17 and CCL20) compared with PI16- Th cells. After 7 day stimulation using CD3 / CD28 beads, PI16+ Th cells produce more IL-17A and less IFN-g compared with PI16- Th cells. PI16+ Th cells also have a higher expression of ROR-gt compared to PI16- Th cells. Furthermore, in comparison to PI16- Th cells, PI16+ Th cells have an increased proliferative potential and are less responsive to suppression by Treg. The memory phenotype of PI16+ Th cells, the high expression of Th17-like chemokine receptors, increased ROR-gt expression and high production of IL-17A suggest an active role of PI16+ Th cells at the site of infection or inflammation. Further studies are ongoing to understand the functional role of PI16 on Th cells in autoimmune and inflammatory diseases.

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