Identification of Th1-polarized Th17 cells: solving the problem

Helper T cells producing IL-17 (Th17) have high plasticity: restimulation of lymphocytes in an inflammatory environment can induce their transformation into cells with another phenotype, and a shift towards Th1 is the most common. The result of this transformation is the appearance of cells expressing along with the classical markers of Th17 cells key Th1-associated molecules. In its most general form, this population is represented by CD4+CD161+CCR6+CXCR3+IL-17+IFNγ+Т cells, and in the current literature it is most often referred to as Th17.1. Some Th17.1 cells can completely lose the production of IL-17, while maintaining the expression of other Th17-associated molecules; these are the so-called ex-Th17 cells (CD4+CD161+CCR6+CXCR3+IL-17- IFNγ+Т cells). Consequently, the population of Th1-polarized Th17 includes Th17.1, ex-Th17 cells and a number of additional transitional forms. It has unique functional properties – an increased pro-inflammatory potential and the ability to overcome histohematic barriers. It is these cells that are currently assigned a key role in the pathogenesis of many autoimmune diseases, and the process of Th17 redifferentiation into Th1 is considered as a promising therapeutic target. However, the development of this direction is complicated by the weak comparability of data on the size of such a population. The analysis of methods for determining Th1-polarized Th17 in vivo and in vitro, carried out in this work, made it possible to resolve these contradictions and develop optimal approaches to identifying this population. In most studies, especially clinical ones, it is identified by co-expression of key cytokines (IL-17/IFNγ) or chemokine receptors (CCR6/CXCR3), rarely by their combination. In this approach, co-expression of CCR6/ CXCR3 marks the total population of Th1-like Th17, including both Th17.1 and ex-Th17, while co-expression of IL-17/IFNγ cytokines identifies only Th17.1 cells, and the subpopulation of ex-Th17 is misclassified as classic Th1 in this case. Such “underestimation” of the ex-Th17 subpopulation significantly marks down the results, since it is ex-Th17 that accounts for the bulk of Th1-like Th17. And only a simultaneous assessment of the co-expression of cytokines and Th17-associated membrane molecules allows identification Th17.1 and exTh17 cells separately, which is important to consider when interpreting data on the problem and when planning clinical trials.