CD4+ T-cell subsets in inflammatory diseases: beyond the Th1/Th2 paradigm

Abstract

CD4(+)T cells are crucial for directing appropriate immune responses during host defense and for the pathogenesis of inflammatory diseases. In addition to the classical biphasic model of differentiation of T-helper 1 (Th1) and Th2 cells, unexpected increases in the numbers of CD4(+)T-cell subsets, including Th17, Th9, T follicular-helper (Tfh) and T-regulatory (Treg) cells, have been recognized. In the present review, we focus on how these various T-helper cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. In particular, we focus on multiple sclerosis, psoriasis and asthma as typical model diseases in which multiple T-helper cell subsets have recently been suggested to play a role. We will also discuss various unique sub-populations of T-helper cells that have been identified. First, we will introduce the heterogeneous T-helper cell subsets, which are classified by their simultaneous expression of multiple key transcription factors. We will also introduce different kinds of memory-type Th2 cells, which are involved in the pathogenesis of chronic type-2 immune-related diseases. Finally, we will discuss the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T-helper cell subsets. The latest progress in the study of T-helper cell subsets has forced us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the Th1/Th2 balance. To this end, we propose another model--the pathogenic T-helper population disease-induction model--as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.

Keywords: T-cell plasticity; Th1/Th2 paradigm; epigenetics; memory Th2 cells; pathogenic Th2 (Tpath2) cells.

Fig. 1.

The heterogeneity of pathogenic T-helper (T_path) cells. Recent advances in research point out several lines of evidence of the heterogeneity of T_path cells, which play a critical role in the pathogenesis of various immune-mediated diseases in an organ-specific manner.

Fig. 2.

A schematic representation of the ‘classical T_h1/T_h2 balance disease-induction model’ and the ‘pathogenic T-helper population disease-induction model’. Since the 1980s, the balance among the T-helper cell subsets has been considered a key component for the pathogenesis of immune-mediated inflammatory diseases such as allergic diseases and autoimmune diseases. In the ‘pathogenic T-helper population disease-induction model’, regardless of the balance among T-helper cell subsets, a pathogenic sub-population of T-helper cells plays a critical role in the pathogenesis of these immune-mediated inflammatory diseases.