Identification of Clec4b as a novel regulator of bystander activation of auto-reactive T cells and autoimmune disease

The control of chronic inflammation is dependent on the possibility of limiting bystander activation of autoreactive and potentially pathogenic T cells. We have identified a non-sense loss of function single nucleotide polymorphism in the C-type lectin receptor, Clec4b, and have shown that it controls chronic autoimmune arthritis in rat models of rheumatoid arthritis. Clec4b is specifically expressed in CD4(+) myeloid cells, mainly classical dendritic cells (DCs), and is defined by the markers CD4(+)/MHCIIhi/CD11b/c(+). We found that Clec4b limited the activation of arthritogenic CD4+alpha beta T cells and the absence of Clec4b allowed development of arthritis already 5 days after adjuvant injection. Clec4b sufficient CD4(+) myeloid dendritic cells successfully limited the arthritogenic T cell expansion immediately after activation both in vitro and in vivo. We conclude that Clec4b expressed on CD4+ myeloid dendritic cells regulate the expansion of auto-reactive and potentially pathogenic T cells during an immune response, demonstrating an early checkpoint control mechanism to avoid autoimmunity leading to chronic inflammation. Author summary To identify early disease regulatory mechanisms in autoimmune diseases such as rheumatoid arthritis (RA) is challenging not only because of the genetic and environmental complexity but also because of the critical autoimmune time-period that precedes the clinical diagnosis. Therefore, we set out to study the complex disease pathways in a more restricted setting. Through genetic segregation of rat crosses, followed by the selection of recombinants to produce minimal congenic strains, we have identified a single nucleotide polymorphism regulating the expression of Clec4b2 that in turn controls the development of arthritis. The Clec4b gene is normally expressed in a population of antigen-presenting cells that can limit enhanced activation of bystander autoreactive T cells during an immune-priming response. This previously unknown type of immune regulation reveals the existence of a mechanism protecting against autoimmune dieases by the avoidance of bystander activation of autoreactive T cells during a normal immune response to foreign antigen.