The Mannose receptor induces T cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Abstract

The present study proves that the mannose receptor (MR) bears beside its function as endocytic receptor a second responsibility namely the induction of tolerance. <br /> The results of our experiments show that the decision, whether this immune-suppressive effect is carried out depends on the inflammatory status of the surrounding milieu. Whereas at steady-state conditions the MR has a tolerogenic effect during activation of CD8⁺ T cells, this suppressive phenotype is overcome under inflammatory conditions. Thereby, the MR resembles a molecular switch between tolerance induction on the one hand and allowance or even mediating immunity by antigen-uptake on the other hand.<br /> The investigations of this thesis shed light into the underlying molecular mechanism of the MR-mediated induction of tolerance. The MR on DCs can bind to the tyrosine phosphatase CD45 on the T cell surface. This interaction leads to inhibition of its phosphatase activity, which is responsible for a reduced cytotoxic capacity of activated CD8⁺ T cells. The executive molecule in this process is the inhibitory protein cytotoxic T-lymphocyte antigen 4 (CTLA-4), being up-regulated upon inactivation of CD45. <br /> After maturation of the DCs with the inflammatory molecule CpG, the immune suppressive effect of the MR is overcome and a robust immune response is initiated. The findings of this study pinpoint this effect to the abolished expression of CTLA-4. It is furthermore shown that signaling events via the co-stimulatory molecule CD28 are sufficient to suppress CTLA-4 up-regulation. Hence, a potent cytotoxic CD8⁺ T cell response is induced.<br /> Finally, it can be demonstrated that the tolerogenic effect of the MR as well as its molecular mechanism also holds true <em>in vivo</em>.