Tracing Functional Antigen-Specific CCR6+ Th17 Cells after Vaccination

Abstract

BackgroundThe function of T helper cell subsets in vivo depends on their location, and one hallmark of T cell differentiation is the sequential regulation of migration-inducing chemokine receptor expression. CC-chemokine receptor 6 (CCR6) is a trait of tissue-homing effector T cells and has recently been described as a receptor on T helper type 17 (Th17) cells. Th17 cells are associated with autoimmunity and the defence against certain infections. Although, the polarization of Th cells into Th17 cells has been studied extensively in vitro, the development of those cells during the physiological immune response is still elusive.Methodology/Principal FindingsWe analysed the development and functionality of Th17 cells in immune-competent mice during an ongoing immune response. In naïve and vaccinated animals CCR6+ Th cells produce IL-17. The robust homeostatic proliferation and the presence of activation markers on CCR6+ Th cells indicate their activated status. Vaccination induces antigen-specific CCR6+ Th17 cells that respond to in vitro re-stimulation with cytokine production and proliferation. Furthermore, depletion of CCR6+ Th cells from donor leukocytes prevents recipients from severe disease in experimental autoimmune encephalomyelitis, a model for multiple sclerosis in mice.Conclusions/SignificanceIn conclusion, we defined CCR6 as a specific marker for functional antigen-specific Th17 cells during the immune response. Since IL-17 production reaches the highest levels during the immediate early phase of the immune response and the activation of Th17 cells precedes the Th1 cell differentiation we tent to speculate that this particular Th cell subset may represent a first line effector Th cell subpopulation. Interference with the activation of this Th cell subtype provides an interesting strategy to prevent autoimmunity as well as to establish protective immunity against infections.

Precarious Balance: Th17 Cells in Host Defense

“…Such activity is consistent with peripheral populations of constitutively activated IL-17-producing T cells observed in uninfected mice and implicates Th17 cells in immune surveillance and the first line of host defense (74). Additionally, IL-17 production has been observed from CD4…”

“…As bacterial burden decreases, phagocytosis of apoptotic but increasingly uninfected neutrophils by DCs may downregulate the Th17-stabilizing cytokine IL-23 (86). Notably, the vaccine-induced kinetics of Th1 and Th17 populations suggest that activation of the IL-17 axis may partially induce a subsequent Th1 response that then attenuates IL-17 production through inhibitory effects of the Th1-produced cytokine gamma interferon (IFN-␥) (43,65,74). On the other hand, abundance of the antiapoptotic protein c-FLIP in Th17 cells decreases their susceptibility to activation-induced cell death, a known mechanism of clearance of Th1 cells (100).…”

CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T‐cell recruitment to target tissues

“…This indicates that CCR6 is not an absolute requirement for disease development; nonetheless, given the delayed onset in CCR6 À/À mice, our data suggest CCR6 influence on an effector-cell population at the onset of disease. CCR6 expression defines functional antigen-specific Th17 cells that induce EAE [20]. Deficiency in IL-17 or in IL-23, which increases or stabilizes IL-17 production, confers partial or complete resistance to MOG-induced EAE in C57BL/6 mice [5,24].…”

“…CCR6 is a common marker of certain tissue-homing Treg [15,16] and Th17 cells [20]; these two cell types show a clear functional dichotomy in inflammatory processes, and both are directly involved in autoimmune disease regulation [18,19]. EAE is thus an excellent model for analysis of the CD4/Th1/Th17/ Treg pathway, and CCR6 À/À mice are useful for determining the function of this receptor in in vivo EAE development.…”

“…Naive T cells develop reciprocally into Treg or pathogenic Th17 cells, depending on the presence or absence of IL-6 in the local cytokine milieu [17][18][19]. The inflammatory environment not only controls T-cell differentiation but also affects Treg suppressor function in the target tissue [9].CCR6 is a common marker of certain tissue-homing Treg [15,16] and Th17 cells [20]; these two cell types show a clear functional dichotomy in inflammatory processes, and both are directly involved in autoimmune disease regulation [18,19]. EAE is thus an excellent model for analysis of the CD4/Th1/Th17/ Treg pathway, and CCR6 À/À mice are useful for determining the function of this receptor in in vivo EAE development.…”