Heather Melichar

In order to recognize diseased and infected cells, T cells require a diverse repertoire of antigen receptors that must distinguish, with exquisite specificity, foreign and mutated antigens from normal self-peptides. Antigen receptor diversity is generated during T cell development in the thymus. Within the thymus, rigorous selection processes accompany T cell differentiation to ensure the functionality and self-tolerance of the unique antigen receptors expressed on individual T cells. Once mature T cells leave the thymus, they encounter a battery of additional checkpoints that regulate their activation in the peripheral lymphoid organs. In addition to their natural role in eliminating abnormal and infected cells, the anti-tumour potential of T cells is being harnessed and re-wired to develop powerful new immunotherapies. Our research program addresses fundamental and translational aspects of T cell development and function. For these studies, we use an array of high-content approaches that allow us to maintain, manipulate, and probe the intact 3-dimensional space of lymphoid tissues. This includes time-lapse imaging of cells in vitro and in situ, mouse and human organotypic culture, genetically engineered mouse models, transcriptome analyses, and multiparametric flow cytometry.

T cell education in the thymus

The enormous diversity of T cell receptor specificities that are required to recognize any foreign or mutated peptide that may be encountered throughout a lifetime is generated during T cell development in the thymus. A possible 10²⁰ different T cell receptors can be produced, but not all T cell receptor gene recombination events are appropriate. We are working to understand how signals through the T cell receptor ensure the generation of a functional, self-tolerant T cell repertoire and also how the interactions between T cells and their environment ultimately influence the quality of the T cell response to infection or cancer.

Predicting T cell fate

Binding of a T cell receptor to antigen leads to a rapid cascade of signaling events that includes increases in intracellular calcium. Differences in calcium levels can lead to distinct transcriptional outcomes. T cell receptor stimulation induces changes in intracellular calcium concentration with temporal dynamics that contain information about T cell receptor affinity for cognate antigen. We have developed collaborations for to perform machine learning analysis of time-lapse images of calcium dynamics in developing and mature T cells to predict developmental and functional outcomes.

Checkpoint modulation of T cell function

T cell function is positively and negatively modulated by co-signaling molecules that belong to the immunoglobulin and tumour necrosis factor receptor superfamilies that have become important therapeutic targets. Manipulation of these checkpoint molecules to invigorate the anti-tumour T cell response has significantly extended the lives of many cancer patients. However, a substantial number of patients receiving these immunotherapies fail to respond. We are interested in defining the immunoregulatory function of orphan tumour necrosis factor receptor superfamily members to identify additional targets within the T cell co-signaling axis to successfully treat a wider range of patients.