The interaction between a specific T cell antigen receptor (TCR) and a peptide-major histocompatibility complex (pMHC) molecule initiates the adaptive immune response. During their brief encounters with potential antigen presenting cells (APC), T cells scan through the matrix of peptide antigens and react with remarkable sensitivity and specificity. Upon antigen recognition, T cells reorganize signaling molecules into a unique structure with segregated protein clusters that is referred to as the immunological synapse. TCR mediated signaling is critical for many downstream events, including large scale changes in gene expression and cell fate determination. While the TCR signaling network has largely been described, the impact of non-coding RNAs (ncRNAs) on this network is largely unknown. Using molecular cell biology techniques, real-time video-microscopy and animal models, the major objective of our laboratory is to better understand how T cells are programmed to generate differential immune responses in the context of ncRNAs. Particular efforts are focused on microRNAs (miRNAs), a novel class of small ncRNAs, that mediate post-transcriptional gene silencing. Currently, we are studying:
1) miR-181a during autoimmune onset and progression. We previously showed that miR-181a targets multiple phosphatases in the TCR signaling network and intrinsically regulates TCR sensitivity at all stages of T cell development. Our more recent work indicates that miR-181a suppression in the thymus will shift the TCR repertoire towards higher affinity T cell clones and generate mature T cells that are self-reactive, which could result in breakdown of central tolerance. We are now addressing the overall impact of this miRNA on adaptive immune responses, especially its relationship with autoimmune dysfunction.
2) miRNAs enhancing or attenuating T cell responsiveness and defining the related molecular mechanisms. In collaboration with Drs. Mark Davis, Chang-Zheng Chen and Yueh-Hsiu Chien’s groups at Stanford University , we identified a large set of miRNAs that are dynamically regulated during T cell development and differentiation. We are now in the process of screening a miRNA expression library to identify and characterize novel miRNAs that can act as modulators of the T cell antigen response.
3) miRNAs that affect immunological synapse formation and examining their related signaling pathways. The immunological synapse is a highly organized macroprotein complex that it is driven by TCR signaling and provides feedback to facilitate that signaling. Our research is aimed at understanding the impact of miRNAs on this spatial and temporal dynamics, identify and verify their relevant protein targets, and explore the functional consequence of miRNA-associated synapse defects.
4) miRNAs that affect mature T cell functional differentiation. Effective adaptive immune responses toward pathogens depend upon the proper differentiation of CD4 T cells into particular effector cell types. Th1 cells are responsible for clearance of intracellular infection and are implicated as the effectors in various autoimmune diseases; Th2 cells control extracellular microbe infection as well as mediate chronic inflammation and allergic responses; and a recently identified third subset, Th17 cells, has been linked to a growing list of autoimmune disorders. Our miRNA cloning experiments indicate that there is dynamic regulation of miRNA expression among these distinct T cell populations, and preliminary results show that overexpression of particular miRNAs can bias effector T cell differentiation. We are now in the process of validating these candidate miRNAs and identifying their target genes, and the role those targets play in T cell differentiation. We will extend the functional studies of these candidates in vivo with animal models of autoimmunity.