Research Projects

A sequential engagement of the cellular and soluble mediators of innate and adaptive immune system is critical for an efficient control of infectious agents and in generating a persisting immunity. Similarly, the durability of vaccine induced immunity is also dependent on the efficiency with which dendritic cells (DCs) interact with T cells. Endowed with features such as dendritic projections, efficient antigen uptake and slower lysosomal degradation of the internalised antigens, DCs are efficient antigen presenters (1) and induce effective primary and memory CD8+ T cell response to control intracellular infection and tumour progression. Therefore, a molecular analysis to understand the functioning of these cells would help design better strategies to boost primary and memory CD8+ T cell response. The members of GTPase of immune associated protein (GIMAP) family are less well-studied proteins in governing the pathophysiological response of immune cells that is the aim of this proposal. This analysis could help better design immunomodulatory therapies. The proposal aims at understanding the role of a small GTPase, GIMAP7 in influencing the development, maturation and dynamics of DCs as well as differentiation of CD8+ T cells during infection of influenza A virus. GIMAPs, earlier known as the immune associated nucleotide (IAN) binding proteins bind GDP/GTP to regulate cellular processes. While all the GIMAPs can bind GTP, GIMAP2 and 5 can also hydrolyze it. GIMAP7 has its own GTPase activity and can also stimulate that of GIMAP2 by interacting with the other partners possibly via a C terminal helical domain. By interacting with each other, the family members could influence the movement of cargo along the cytoskeletal network (2). GIMAPs encoding genes span a region of ~500kb on chromosome 7 which also harbors several immune associated genes indicating their co-evolution. Mutation in GIMAP5 is associated with the lymphopenia and skewing of the ratios of CD8+ and CD4+ T cells suggesting their role in maturation, survival or the homeostatic turnover of T cells possibly via impaired TCR or the IL-7R mediated signaling (3). GIMAP1 depletion compromises cellular survival by enhancing mitochondrial potential and reduces O2 consumption (4). GIMAP4 mediates enhanced apoptotic cell death and GIMAP6 is involved in an autophagic response (5). GIMAP7 is known to localize in intracellular organelles such as lysosomes and vesicles and it is involved in inactivating glycogen synthase kinase 3-beta (GSK-3) by inhibiting cellular proliferation, differentiation, survival and cellular motility but its role in immune cells has not been investigated (6). How GIMAP7 influences immune cells is not known. The study is conceptualized based on our preliminary analysis of RNAseq data of DCs and the responding virus-specific CD8+ T cells isolated from mice which revealed a preferential upregulation of GIMAP7. We observed a differential expression of several GIMAPS in CD8+ T cells isolated from animals in the acute phase of a viral infection. GIMAP7 showed the highest fold change in the expression level. Similarly, splenic DCs expressed the molecule but its expression is 3-fold higher in those from aged as compared to the control mice. What role GIMAP7 plays in DCs has not been studied. Given its localization in ER and cytosol, the molecule is likely involved in controlling the innate functions of DCs that we plan to decipher in the proposed study. Furthermore, a GIMAP7 specific nanobody has been generated from an in-house constructed phage display library which would not only be used for analyzing its expression kinetics but also in fine tuning the GIMAP7 response intracellularly. The proposal would also serve to establish GIMAP7 as a target for modifying the functionality of these cells to achieve favorable outcome of diseases.