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

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 (T(h)1) and T(h)2 cells, unexpected increases in the numbers of CD4(+) T-cell subsets, including T(h)17, T(h)9, T follicular-helper (T-fh) and T-regulatory (T-reg) 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 T(h)2 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 T(h)1/T(h)2 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.