T cell development and selection throughout the lifespan

T cells coordinate adaptive immune responses against the myriad pathogens and newly arising tumors encountered throughout life. To accomplish highly specific recognition of diverse pathogens and tumors, each T cell expresses a unique T cell receptor (TCR) that is encoded by randomly and imprecisely rearranged gene segments. This process of gene rearrangement has been estimated to generate as many as 10^18 different TCRs! By chance, some of these TCRs will recognize this year’s flu strain or SARS-CoV-2, for example, thus enabling an immune response against any pathogen encountered. However, also by chance, some TCRs will recognize our body’s own proteins, and such autoreactivity can lead to autoimmune disorders. To ensure that the T cell repertoire is diverse but not auto-reactive, T cells undergo rigorous selection processes in the thymus, the organ in which T cells differentiate throughout life. One of my laboratory’s major research goals is to identify the cellular and molecular interactions between developing T cells and the heterogeneous stromal cells in the thymus microenvironment that govern generation of diverse but non-autoreactive T cells throughout the lifespan.

We employ a variety of experimental approaches to investigate T cell development in genetically modified mouse models. We use time-lapse two-photon microscopy to investigate thymocyte: stromal cell interactions in live tissue, single-cell and bulk transcriptional profiling of thymocyte and stromal cell subsets to identify candidate genes that impact T cell differentiation and selection, multi-parameter flow cytometry and multiplex immunofluorescence analysis of lymphoid tissues to assess the impact of different genes on T cell differentiation and localization, and in vitro cellular immunology assays to assess the impact of genes/pathways on lymphocyte activation.

The contribution of the tumor microenvironment to T-ALL

T cell acute lymphoblastic leukemia (T-ALL) is a common pediatric cancer that arises when developing T cells in the thymus proliferate and survive in an uncontrolled manner. Using mouse models of T-ALL, we have discovered that T-ALL blasts cannot survive on their own, but instead require supportive signals from the tumor microenvironment. Identifying the cellular and molecular mechanisms by which the microenvironment supports T-ALL would reveal novel candidate targets for therapeutic intervention. We have found that myeloid cells, a heterogeneous group of immune cells present in all organs, support initiation and progression of T-ALL in mouse models and in pediatric patients. We have identified several mechanisms underlying myeloid-mediated T-ALL support in the thymus, where T-ALL arises, as well as in other organs later infiltrated by T-ALL. We are currently using bulk and single-cell transcriptional profiling, proteomics, imaging, and a combination of in vitro and in vivo assays to comprehensively identify myeloid cell types and associated signals responsible for supporting T-ALL progression in the thymus and other leukemic organs. The goal of these studies is to identify novel targets in the T-ALL tumor microenvironment for therapeutic intervention to improve patient outcomes.

Immune correlates of disease severity in COVID-19 patients

Since the outbreak of SARS-CoV-2 in December of 2019, more than 1 million individuals have died from COVID-19 in the United States alone. However staggering, this number represents only about 1% of COVID-19 cases, as most individuals experience milder disease and recover. We hypothesize that improperly regulated immune responses to SARS-CoV-2 in some patients result in tissue damage leading to death. We are currently collaborating with the Melamed lab at Dell Medical School to investigate immune correlates of disease severity in COVID-19 patients across the lifespan. Understanding why/how the immune response is sometimes protective and sometimes overtly damaging will enable rational design of therapies to modulate the immune response to ensure viral clearance while protecting patients from severe disease. In keeping with our interests in understanding the delicate balance between maintaining a diverse repertoire while avoiding autoimmunity, we are also studying links between SARS-CoV-2 infection and autoimmunity.