Cell fate decisions shaping T cell immunity

Cell fate decision making is a frequent event facing most T cells in our body. Developmentally, abT cells which comprise the majority of T cells in our body, commit to becoming CD4⁺ helper or CD8⁺ cytotoxic T cells from a common bipotent precursor. Critical signals received at the time of commitment influence these cell fate outcomes. Importantly, signals received during the commitment process also impart vital epigenetic features that allow fully developed cells to maintain their identity in the periphery in a heritable manner. Using endogenous and physiological genetic tools to study a model gene Cd4, we recently demonstrated that TCR-signaling duration and intensity is paramount for error-free lineage commitment of T cells to the helper T cell lineage. Interruption or a reduction in CD4-mediated TCR signaling can lead to redirection of MHC-II restricted T cells into the cytotoxic lineage. Additionally, TCR-signaling is concomitant with heritable epigenetic changes at distinct loci associated with lineage identity of helper T cells.  

Figure 1

Notably, lineage commitment in the thymus is not an identity end-point for helper and cytotoxic T cells. For many years it has been recognized that during both the effector and the memory phase, antigen-specific T cell populations develop substantial phenotypic and functional diversity. Some of these features are heritable, others are transient in nature. As the generation of different T cell subsets during infection or in response to vaccination is key for the quality of antigen-specific immunity, in the lab we are interested in understanding a) the signals that govern T cell commitment and b) the intrinsic epigenetic mechanisms that confer heritable signatures.

To address these, we study fundamental mechanisms that dictate T cell development using the thymus as a model as well as employ various mouse models of infections to dissect mechanisms that shape effector and memory responses in the periphery. 

Figure 2

Epigenetic processes and Transcription

In the course of our studies looking at lineage commitment of helper CD4 T cells, using a model locus associated with helper T cell identity, we discovered that regulatory cis-elements are intimately involved in shaping the epigenetic landscape of gene transcription. Regulatory cis-elements, which can be in the form of enhancers and silencers, offer temporal control of gene expression and by dictating the timing of gene expression, are able to significantly alter the course of cell differentiation. In addition, they appear to impart key epigenetic features that continue to affect transcription, even when they are no longer active. With the aid of new mouse models and whole genome sequencing technologies, we are exploring the link between regulatory cis-elements and epigenetic remodeling, with the aim of understanding how such mechanisms may be relevant in immunological disease.

Inactive Rhomboids and ADAMs (Joint focus with Maretzky Lab)

As a joint collaboration with the Maretzky Lab, we pursue studies looking at the role of an intriguing group of inactive proteases known as the inactive rhomboids, iRhoms, and their modulation of innate and adaptive immune responses in mice. iRhoms are catalytically dead homologues of their active counterparts, the rhomboid proteases: a group of intramembrane serine proteases that mediates the proteolytic cleavage of membrane‐tethered ligands in Drosophila. However, the conserved function of rhomboids in flies seems to have diverged in mammals whereby they have lost their catalytic function but remarkably, iRhoms are evolutionarily conserved and present in all metazoans and control key signaling pathways such as EGFR signaling and TNF signaling. The two mammalian homologs, iRhom1 and iRhom2 exhibit tissue‐restricted expression and the joint focus of the Maretzky/Issuree labs is a) to understand the molecular aspects controlling tissue-specific expression and function of iRhoms and b) to evaluate the respective roles of iRhom1 and 2 in modulating inflammation and immunity using mouse models.

Visit Dr. Maretzky's lab: https://maretzky.lab.uiowa.edu