The roles of STRA6, EFNB1/B2 and ARMC5 in T cell function and autoimmune diseases

Receptor tyrosine kinases are a group of key signaling molecules, which have dual functions: sensing the environmental stimuli outside the cells and transmitting them into the cells. 20 years ago, our laboratory started to study the function of Ephb6 kinase, a receptor tyrosine kinase highly expressed in T lymphocytes. As both Efnb1 and Efnb2 are the ligands for Ephb6, we then proceeded to study their roles in T cell function in vitro and in vivo. T cellspecific Efnb1, Efnb2 single gene knockout (KO), as well as Efnb1/b2 double KO mice were generated, but only the double KO mice showed compromised thymocyte development, Th1 and Th17 function, IL-6 receptor signaling, and anti-virus responses. Strong evidence indicates that T cells play a crucial role in the pathogenesis of rheumatoid arthritis (RA). Thus, we postulated that T cell-specific Efnb1/b2 double KO in mice may protect mice from collagen-induced arthritis (CIA), a mouse model for human RA. We found that Efnb1 and Efnb2 in T cells were essential for pathogenic antibody production and T cell migration to the inflamed paws in mice with CIA. Our clinical study suggests that the expression of EFNB1 in T cells might be a useful parameter for monitoring RA disease activity and treatment responses. Naïve T cells have the ability to expansion and differentiation into effector cells once they encounter foreign antigens, during which a large number of molecules are modulated. Some of these molecules play essential regulatory roles, while others exert house keeping functions and/or act as supporters to cope with increased or changed metabolic demands. To fully elucidate events in the T cell activation program, we undertook unbiased exploration with DNA microarray analysis to identify molecules that were differentially expressed in WT versus Ephb6 KO T cells in the early T-cell activation stage. About 30 molecules were up- or down-regulated more than three folds in WT T cells compared with KO T cells. Stra6 (stimulated by retinoic acid gene 6) and Armc5 (Armadillo repeat-containing 5) were among those that had been validated for their altered expression. We generated mice with these two genes deleted to study their roles in T cell function in vitro and in vivo. STRA6 is a high-affinity receptor for plasma retinol-binding protein (RBP) and mediates cellular vitamin A uptake. Stra6 KO mice manifest normal spleen and thymus in size, cellularity and lymphocyte subpopulations. KO and WT T cells were similar regarding proliferation, differentiation and anti-viral immune responses to lymphocytic choriomeningitis virus (LCMV). Thus, the up-regulation of Stra6 is either a parallel event which is not essential for the T cell activation program or it is so critical that heavy redundancy exists. ARMC5 is an intracellular protein containing seven tandem armadillo repeats and one BTB domain. Functions of ARMC5 in the immune system are not known previously. Our in situ hybridization results showed high expression of Armc5 in the thymus and moderate expression in the spleen and lymph nodes. A transient increase of Armc5 expression in T cells after TCR activation was found. To investigate its roles in T cell function, Armc5 KO mice were generated. The KO mice weighed 40% less than their WT counterparts. Lymphoid organs (the thymus, spleen and lymph nodes) of the KO mice appeared to be of normal size, weight, cellularity, and lymphocyte subpopulations. Intriguingly, Armc5 KO T cells presented decreased proliferation and compromised differentiation towards Th1 and Th17 in vitro. The KO mice were resistant to experimental autoimmune encephalitis induction and were compromised in anti-LCMV immune responses. Using yeast 2-hybrid assay, we have identified 8 ARMC5-assciating proteins, which have known functions in cell cycling and apoptosis. Further mechanistic study is underway. Our results reveal that Armc5 is vital in the T cell activation/proliferation /differentiation program. Our studies have augmented our knowledge about EFNB1, EFNB2, STRA6 and ARMC5 in T cell biology and their relevance to immune disorders in animal models as well as in humans.

Keyphrases: EFNB1, EFNB2, STRA6, ARMC5, T cells, Rheumatoid arthritis, Multiple sclerosis