A Study on the C-Type Lectin Receptor CD302 Reveals a Role in Dendritic Cell Migration and Its Potential as A Therapeutic Target for Acute Myeloid Leukaemia

Abstract

C-type lectin receptors (CLR) play important roles in immune cell interactions with the environment. We described CD302 as the simplest type I CLR, which is restricted to myeloid cells in human blood. CD302 colocalised with cell migratory structures including podosomes and lamellopodia, leading us to hypothesise that this CLR contributes to cell migration. This thesis describes the use of mouse models to obtain further insights into CD302 expression and immunological function. Akin to humans, mouse CD302 transcripts were highest in liver, lungs, lymph nodes (LN), spleen, and bone marrow. Detailed analysis of CD302 transcription in immune cells revealed high expression by macrophage (Mϕ), granulocytes and myeloid dendritic cells (mDC). Greater CD302 expression was found in migratory compared to resident mDC. We generated the first CD302 knockout (CD302KO) mouse and revealed a decrease in migratory mDC within LN of these animals. CD302KO migratory DC exhibited reduced in vivo migration into LN interfollicular channels, establishing a role for CD302 in mDC migration. CD169+ Mϕ in LN subcapsular sinus also showed irregular distribution. Monoclonal antibodies have been shown effective in the treatments of different haematological malignancies. However, acute myeloid leukaemia (AML) targets are currently limited so discovery of new targets would be beneficial to patients. We found expression of CD302 on the surface of blasts in the vast majority of AML patients. More importantly, CD302 was positive on leukaemic stem cells, the population responsible for relapse of the disease. Monoclonal antibodies targeting human CD302 were effective in mediating antibody dependent cell cytotoxicity and were internalised, making them amenable to toxin conjugation. Targeting CD302 with antibodies also limited in vivo engraftment of the leukaemic cell line HL-60 in NOD/SCID mice. These studies provide the foundation for studies examining CD302 as a potential therapeutic target for AML.