T helper subset development: roles of instruction, selection, and transcription.

Abstract

The past 15 years have seen the development of a field in immunology entirely devoted to understanding the divergence of CD4+ T cells into distinct cytokine-producing subsets. Generally speaking, the immune response to a pathogen can develop toward a more strongly cellular type (type 1), or toward a more allergic type of response (type 2). When well developed, these gear the immune response for the effective elimination of different types of pathogens, with a type 1 response being more effective against intracellular pathogens, for example Listeria monocytogenes or mycobacteria. Type 2 allergic responses, in contrast, favor the elimination of parasites such as helminths. The basis for this selective action resides in the cytokines made by the CD4+ T helper cell subsets in these responses. T helper type 1 (Th1) cells produce several characteristic cytokines, most notably IL-2 and IFN-γ, whereas Th2 cells produce a set of cytokines, most notably IL-4, IL-5, and IL-13. In turn, IL-2 and IFN-γ promote the development of strong cell-mediated immunity, whereas the type 2 cytokines promote allergic responses effective in eliminating parasites. When confronted with a pathogen, it is important that the immune system activate the appropriate type of response. Fortunately, it has developed reliable mechanisms that help naive CD4 T cells in this choice. These mechanisms have been fairly well worked out at many levels over the last decade, and several thorough reviews have described recent findings regarding the signaling pathways and transcription factors that contribute to peripheral CD4+ Th development (1–3). Despite the great progress in the molecular understanding of these processes, there are still issues in this area that are controversial and actively debated. Here, we will focus on some aspects that are unresolved within the various models of Th1 and Th2 development and will try to fit together some of the recent observations that have motivated these somewhat theoretical considerations. In particular, we will take this opportunity to focus on a difficult topic, that of whether Th1/Th2 development rests on selective or instructive mechanisms, a general issue that is also debated in regard to CD4/CD8 lineage commitment and is common to many developmental systems. Distinguishing between strictly selective and instructive models is difficult, as many experimental results can be compatible with both interpretations.