Heather Melichar
Associate Professor
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.
This, S., Costantino, S.#, and Melichar, H.J.# (2024) Machine learning predictions of T cell antigen specificity from intracellular calcium dynamics. Science Advances, 10:eadk2298.
Textor, J.#, Buytenhuijs, F., Rogers, D., Mallet Gauthier, È., Sultan, S., Wortel, I.M.N., Kalies, K., Fähnrich, A., Pagel, R., Melichar, H.J., Westermann, J., and Mandl, J.N.# (2023) Machine learning analysis of the T cell receptor repertoire identifies sequence features of self-reactivity. Cell Systems, 14, 1059-1073.e5.
This, S.*, Rogers, D.*, Mallet Gauthier, È., Mandl, J.N.#, and Melichar, H.J.# (2023) What's self got to do with it: sources of heterogeneity among naive T cells. Seminars in Immunology, 65, 10172
Artusa, P., Lebel, M-È., Barbier, C., Memari, B., Salehi-Tabar, R., Karabatsos, S., Ismailova, A., Melichar, H.J.#, White, J.# (2023) Autoimmune regulator (AIRE) is a coactivator of the Vitamin D receptor. The Journal of Immunology, 211: 175-179.
Sood, A.*, Lebel, M-È.*, Dong, M., Fournier, M., Vobecky, S.J., Haddad, É. Delisle, J-S., Mandl, J.N., Vrisekoop, N.#, and Melichar, H.J.# (2021) CD5 levels define functionally heterogeneous populations of naïve human CD4+ T cells. European Journal of Immunology, 51, 1365-1376.
Rogers, D., Sood, A., Wang, H.C., van Beek, J.J.P., Rademaker, T.J., Artusa, P., Schneider, C., Shen, C., Wong, D.C., Lebel, M-È., Condotta, S.A., Richer, M.J., Martins, A.J., Tsang, J.S., Barreiro, L., Francois, P., Langlais, D., Melichar, H.J., Textor., J., and Mandl, J. (2021) Pre-existing chromatin accessibility and gene expression differences among naive CD4+ T cells influence effector potential. Cell Reports, 37, 110064
Dong, M., Audiger, C., Adegoke, A., Lebel, M-È., Anderson, C., Melichar, H.J.#, and Lesage, S.#, (2021) CD5 levels reveal distinct basal T-cell receptor signals in T cells from non-obese diabetic mice. Immunology & Cell Biology, 99, 656-667.
Lebel, M-È., Coutelier, M., Galipeau, M., Kleinman, C.L., Moon, J.J., and Melichar, H.J. (2020) Differential expression of tissue restricted antigens among mTEC is associated with distinct autoreactive T cell fates. Nature Communications, 11, 3734.
Sood, A., Lebel, M-È., Fournier, M., Rogers, D., Mandl, J.N., and Melichar, H.J. (2019) Differential interferon-gamma production potential among naïve CD4+ T cells exists prior to antigen encounter. Immunology & Cell Biology, 97, 931-940.
Dong, M., Artusa, P., Kelly, S.A., Fournier, M., Baldwin, T.A., Mandl, J.N., and Melichar, H.J. (2017) Alterations in the thymic selection threshold skew the self-reactivity of the T cell receptor repertoire in neonates. The Journal of Immunology,199, 965-973.
Halkias, J., Yen, B., Reinhartz, O., Taylor, K.T., Winoto, A., Robey, E.A., and Melichar, H.J. (2015) Conserved and divergent aspects of human T cell development and migration in humanized mice. Immunology & Cell Biology, 93, 716-726.
Au-Yeung, B.B.*, Melichar, H.J.*, Ross, J.O., Cheng, D.A., Zhang, C., Shokat, K.M., and Robey, E.A., and Weiss, A. (2014) Quantitative and Temporal Requirements Revealed for Zap-70 catalytic activity during T cell development. Nature Immunology, 15, 687-694.
Ross, J.O.*, Melichar, H.J.*, Au-Yeung, B.B., Herzmark, P., Weiss, A., and Robey, E.A. (2014) Two distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and TCR signaling patterns. Proceedings of the National Academy of Sciences, 111, E2550-2558.
Halkias, J.*, Melichar, H.J.*, Taylor, K.T., Ross, J.O., Yen, B., Cooper, S.B., Winoto, A., and Robey, E.A. (2013) Opposing chemokine gradients control human thymocyte migration in situ. Journal of Clinical Investigation, 123, 2131-2142.
Melichar, H.J.*, Ross, J.O.*, Herzmark, P., Hogquist, K.A., and Robey, E.A. (2013) Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Science Signaling, 6, ra92.
Melichar, H.J., Narayan, K., Der, S., Hiraoka, Y., Gardiol, N., Jeannet, G., Held, W., Chambers, C., and Kang, J. (2007) Regulation of gd versus ab T lymphocyte differentiation by the transcription factor Sox13. Science, 315, 230-233.
Link to full list of Dr. Melichar's publications: