Complement and Invariant NKT Cell Response

The complement system forms an integral part of the immune system, comprising over 30 soluble and cell surface proteins. Complement behaves as a key mediator of the general inflammatory response, but also forms a functional bridge between the short-term innate and long-term adaptive immune responses. Although a vast breadth of knowledge exists on the role of complement signalling in both B and T lymphocytes (key cell types involved in the adaptive immune response), their role in invariant Natural Killer T (iNKT) cell responses is as yet poorly defined.
Although iNKT cells comprise a very small population of cells, approximately 0.1% of total lymphocytes in the blood of healthy individuals; their immuno-regulatory potential should not be underestimated. For example, it has previously been demonstrated that cognate engagement of the complement receptor C5aR on the surface of iNKT cells promotes a septic phenotype in vivo following E.coli infection. Moreover, genetic deletion of this receptor reduces the activation of such cells, which in turn correlates with improved survival in vivo.
Upon antigenic stimulation, iNKTs secrete multiple cytokines. Cytokines are small soluble proteins or glycoproteins which encompass a diverse range of protein sub-families including interferon, interleukin and growth factors. They exert both pro- and anti-inflammatory actions both within their local microenvironment, but also in a more widespread manner through interactions with their cognate receptors on other cell types.
Two distinct pathways have been observed regarding iNKT cell activation. Invariant NKT cells recognise microbial and endogenous lipid antigens which in turn are presented by antigen-presenting cells, mainly dendritic cells (DCs). This microbial antigen-driven pathway enables direct recognition of the antigen by the iNKT cell through its surface receptor termed the TCR (T-cell receptor). However, it has more recently been demonstrated that full iNKT cell activation requires cytokine signalling. More specifically, activation can be achieved by a weak TCR-mediated signal (i.e. lipid antigen) in association with interleukin-12 (IL-12). It has also been observed that under certain circumstances, IL-12 and IL-18 signalling alone is sufficient to drive iNKT cell activation, thus bypassing the requirement for direct recognition of lipid antigen. This intriguing finding sheds new light on how iNKT cells are able to respond to a disparate number of microbial antigens and hence become activated, even though the diversity of their actual TCR is quite limited.
Although the importance of cytokine signalling in iNKT cell activation is well defined, a similar concept regarding complement fragment-cognate receptor signalling is as yet undefined. This project will attempt to determine if complement, in a manner similar to cytokines, can trigger iNKT cell activation and whether this signalling can modulate their effector responses. The initial identification of complement receptors on iNKT cells will be followed by functional assays to delineate between different effector responses. This work will subsequently be translated in vivo in an attempt to determine if modulation of complement signalling holds any clinical relevance.