T cell homeostasis: disturbed in autoimmune diseases?

Abstract

Based on all data gathered in this thesis, combined with findings of other groups, we designed a hypothesis on the possible role of CD4+CD28- T cells in MS (Figure 6.1). In peripheral lymphoid tissues of CMV infected individuals or persons with an (auto-)immune disorder, CD4+ T cells lose CD28 as a result of chronic stimulation (175). This way, CD4+CD28- T cells arise. This cell population has cytotoxic and inflammation-seeking properties and an effector-memory phenotype (168). In the serum of MS patients, IL-15 was shown to be upregulated. We found that IL-15 preferentially induced proliferation of CD4+CD28- T cells, further expanding this cell population. IL-15 also increases the expression of chemokine receptors (including CX3CR1) and adhesion molecules on these cells, potentiating their migratory capacity to the CNS. The levels of both IL-15 and fractalkine are increased in the CNS of MS patients, creating a gradient from the periphery to the CNS. CD4+CD28- T cells migrate via these gradients (mainly fractalkine) to the CNS, crossing the BBB and entering the perivascular space. Here, these cells are reactivated by their cognate antigen (either a myelin or mimetic antigen), resulting in cytokine production. Two of these products, namely IL-1β and IL-6, aid the IL-23 driven differentiation of naive CD4+ T cells to IFN-γ/IL-17A double-producing cells, which are increased in MS lesions. Another product of CD4+CD28- T cells, namely CXCL1, is shown to inhibit remyelination and repair after demyelination. In the perivascular space, infiltrating immune cells (most likely monocytes) express membrane-bound IL-15. This leads to further activation of CD4+CD28- T cells, and upregulation of cytotoxic molecules. When CD4+CD28- T cells enter the brain parenchyma, IL-15 can still be transpresented to them by astrocytes. NKG2D is upregulated in response to IL-15, and NKG2D ligand expressing oligodendrocytes are present in MS lesions (269). In addition to TCR triggering, binding of NKG2D on CD4+CD28- T cells provides costimulation to these cells. This leads to degranulation and secretion of perforin and granzyme B, causing cytolysis of oligodendrocytes expressing NKG2D ligands and consequently, demyelination.