Figure 2.

Hypothetical Mechanism of Competition between Protective Central Memory T Helper Type 1 (Th1_CM) and Pathogenic Th1/17_CM Cells. (A) Th1_CM and Th1/17_CM cells express increased levels of the transcription factor T-bet, which induces the expression of the IL-2/15Rβ-chain that renders T cells responsive to the homeostatic cytokine IL-15, which is required to maintain antiviral CD4 memory in the absence of antigen. (B) In healthy individuals (i) Th1_CM and Th1/17_CM cells are in equilibrium, and both compete successfully for IL-15, which is most abundant in peripheral tissues, but is also produced by stromal and epithelial cells in lymph nodes. In addition, they occasionally interact with dendritic cells (DCs) in lymph nodes and sense self-major histocompatibility complexes (MHCs). In patients with multiple sclerosis (MS) (ii) autoreactive Th1/17_CM cells could expand at the cost of virus-specific Th1_CM cells, because they proliferate with self-MHC-presenting DCs in lymph nodes during the remission phase. In addition, natalizumab could limit the access to IL-15 in peripheral tissues and, thus, intensify competition. However, while Th1/17_CM cells might have preferential access to IL-15 that is trans-presented on IL-15Rα by DCs (iii), Th1_CM cells might be less fit under these conditions and die by neglect.