Th1 and Th17 cells: adversaries and collaborators

Abstract

Autoreactive effector CD4+ T cells have been associated with the pathogenesis of autoimmune disorders. Early studies implicated the interferon (IFN)-gamma-producing T helper (Th)1 subset of CD4+ cells as the causal agents in the pathogenesis of autoimmunity. However, further studies have suggested a more complex story. In models thought to be driven by Th1 cells, mice lacking the hallmark Th1 cytokine IFN-gamma were not protected but tended to have enhanced susceptibility to disease. Identification of the IL-17-producing CD4+ effector cell lineage (Th17) has helped shed light on this issue. Th17 effector cells are induced in parallel to Th1, and, like Th1, polarized Th17 cells have the capacity to cause inflammation and autoimmune disease. This, together with the finding that deficiency of the Th17-related cytokine IL-23 but not the Th1-related cytokine IL-12 causes resistance, led to the notion that Th17 cells are the chief contributors to autoimmune tissue inflammation. Nevertheless, mice lacking IL-17 are not protected from disease and display elevated numbers of IFN-gamma-producing CD4+ T cells, and, in some cases, lack of IFN-gamma does confer resistance. Recent studies report overlapping as well as differential roles of these cells in tissue inflammation, which suggests the existence of a more complex relationship between these two effector T-cell subsets than has hitherto been suspected. This review will attempt to bring together current information regarding interaction, balance, and collaborative potential between the Th1 and Th17 effector lineages.

Figure 1

Conditions of initial exposure to antigen (Ag) affect effector dominance in vivo (modified from Luger et al.5). Schematic representation of the quality/quantity of Toll-like receptor (TLR) signals and the type/variety of cells participating as antigen-presenting cells (APCs) as factors affecting effector T-cell dominance in two different experimental autoimmune uveitis (EAU) models. TLR = toll-like receptor; IRBP = interphotoreceptor retinoidbinding protein; CFA = complete Freund’s adjuvant; LTA = lipoteichoic acid; DC = dendritic cell; B = B cell;M0 = macrophage; gd T = gamma delta T cell; LPS = lipopolysaccharide.

Figure 2

Sequential recruitment of effector T cells into the target organ during inflammation (reprinted with permission from Dardalhon et al.79). In secondary lymphoid tissues, IL-6 together with transforming growth factor (TGF)-β can induce IL-21 production from IL-17-producing T cells. IL-21 then functions in an autocrine self-amplification loop to increase the T helper (Th)17 response. The maintenance of already committed Th17 cells requires IL-23. Th17 cells would then constitute the first wave of effector T cells migrating to the target tissue. IL-17 secretion will induce the expression of different chemokines, which could drive the migration of further waves of effector T cells and also mononuclear cells. Finally, this change in the composition of the effector T cells toward Th1 contributes to resolution of tissue inflammation by regulatory T cells (Tregs). IFN-γ, interferon-γ.