Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23

Abstract

Interleukin-23 (IL-23) is essential for the differentiation of pathogenic effector T helper 17 (Th17) cells, but its role in memory Th17 cell responses is unclear. Using the experimental autoimmune encephalomyelitis (EAE) model, we report that memory Th17 cells rapidly expanded in response to rechallenge and migrated to the CNS in high numbers, resulting in earlier onset and increased severity of clinical disease. Memory Th17 cells were generated from IL-17+ and RORγt+ precursors, and the stability of the Th17 cell phenotype depended on the amount of time allowed for the primary response. IL-23 was required for this enhanced recall response. IL-23 receptor blockade did not directly impact IL-17 production, but did impair the subsequent proliferation and generation of effectors coexpressing the Th1 cell-specific transcription factor T-bet. In addition, many genes required for cell-cycle progression were downregulated in Th17 cells that lacked IL-23 signaling, showing that a major mechanism for IL-23 in primary and memory Th17 cell responses operates via regulation of proliferation-associated pathways.

Opposing Effects of CTLA4 Insufficiency on Regulatory versus Conventional T Cells in Autoimmunity Converge on Effector Memory in Target Tissue

“…These autoimmune CD4 + T EM cells were also potent producers of pathogenic cytokines like IFNγ and IL17 with the IL17 being produced only within the CD4 + T EM compartment. This is in contrast to an acute infection model where only short lived CD4 + T EFF cells produce IL17 (49) and supports the notion of autoimmune Th17 memory as has been recently shown (50). Unlike in chronic infections and a model of skin autoimmune disease, where persistence of antigens impairs cytokine production in the target tissue (5, 51), these autoimmune CD4 + T EM cells produced as much IL17 and IFNγ in the pancreas as they did in the draining lymph nodes.…”

Apoptotic cell-treated dendritic cells induce immune tolerance by specifically inhibiting development of CD4+ effector memory T cells

“…Moreover, Egwuagu et al reported that auto-reactive memory CD4 + T cells play an important role in chronic uveitis and their immigration to bone marrow is dependent on signal transducer and activator of transcription 3 (STAT3)-mediated pathways [31]. Moreover, Haines’ results demonstrated that autoimmune memory Th17 cell-mediated inflammatory responses in EAE mice are regulated by IL-23-mediated pathways [32]. Elyaman et al found that development of EAE can be facilitated by pro-inflammatory memory CD4 + T cells [33].…”

The Special Relationship in the Development and Function of T Helper 17 and Regulatory T Cells

“…37 However, while Th17 cells that are generated in the presence of TGF-β and IL-6 are only weakly pathogenic and express significant levels of , it has become clear that presence of IL-23 is critical for the differentiation of pathogenic Th17 cells. 37,39,40 In fact, it is very likely that the in vivo environment and the presence of specific factors and cytokines govern a high degree of functional plasticity within the Th17 lineage. In that respect, it has been shown recently in a model of anti-CD3-induced intestinal inflammation that Th17 cells can be re-directed into a regulatory phenotype.…”