Biology of the Immune System
The various compartments of the immune system make up what is perhaps the most intriguing and intricate cellular network aside from the nervous system. Through the targeted mutation of individual genes, our laboratory has endeavoured to dissect the function of its various components, one molecule at a time.
To achieve this goal, we have generated mice lacking the key receptors, co-receptors and signaling molecules that participate in T cell development, activation and differentiation. To understand signal transduction through the T cell receptor (TCR) complex, animals lacking the tyrosine kinase Lck, the tyrosine phosphatase CD45, or the adaptors Bcl-10 or MALT1 have been generated.
Lck is essential for the transduction of receptor proximal signals, while CD45 promotes Lck activity. Bcl10 and MALT1 appear to cooperate in a signalling complex that specifically links antigen receptor engagement to activation of the cell survival transcription factor NF-kB. The activation of NF-kB depends on the degradation of an inhibitory binding protein called IkB. We generated mice lacking NEMO, a scaffolding subunit of the IKK complex responsible for phosphorylating IkB and promoting its degradation. NEMO-deficient mice die of severe liver damage due to a lack of NF-kB-driven transcription of protective genes.
To gain further insights into the co-stimulatory signalling essential for normal T cell activation, mice lacking the positive regulator CD28 and the negative regulator CTLA4 have been studied. Animals lacking the inducible co-stimulator ICOS or its counter-receptor B7RP-1 have also been generated, revealing the multiple layers of control of T cell differentiation and effector function. Recent work in this area has established that B7-H3 is a selective negative regulator of Th1 responses.
Differentiation of effector T cells also requires the receipt of certain cytokine signals, as clarified by study of mice deficient for subunits of the interleukin-2 receptor. In the absence of IL-2Rb, mice exhibit dysregulated T cell activation and autoimmunity. Mice lacking WSX-1, a cytokine receptor homologous to IL-12R, show a delay in the mounting of Th1 responses. Members of the interferon regulatory factor (IRF) family of transcription factors also have regulatory effects on immune responses. We identified IRF2 as a lymphocyte-specific family member that is essential for B and T cell activation and for the development of NK and Th1 cells. In contrast, IRF-4 is required for the expression of the transcription factor GATA-3 that governs Th2 responses.