Spatial and temporal dynamics of immune cell interactions

Abstract

In this thesis, I explore spatial and temporal methods for studying immune cell interactions.

First, I review Slide-TCR-seq, a method we developed for measuring T cell receptor (TCR) sequences in the tissue context. T cells mediate antigen-specific immune responses to disease through the specificity and diversity of their clonotypic TCRs. We confirmed the ability of Slide-TCR-seq to map the characteristic locations of T cells and their receptors in mouse spleen. In human lymphoid germinal centers, we identified spatially distinct TCR repertoires. Profiling T cells in renal cell carcinoma and melanoma specimens revealed heterogeneous immune responses: T cell states and infiltration differed intra- and inter-clonally, and adjacent tumor and immune cells exhibited distinct gene expression. Our method yields insights into the spatial relationships between clonality, neighboring cell types, and gene expression that drive T cell responses.

Second, I will discuss an application of Slide-TCR-seq to study immunological aging in the thymus in human and mouse contexts, as well as strategies for regeneration. Humans have elaborate immune defenses to protect against infectious agents and the damage they cause. The thymus is a key part of the immune system, providing a unique environment for developing T cells, and contributing to the recognition and destruction of intracellular pathogens. During development, precursors of T cells migrate from the bone marrow to the thymus, where they undergo maturation and selection, leading to a vast repertoire poised to recognize and clear foreign pathogens. In mammals, this process of T cell maturation occurs early in development, and as the animals age, the thymus gradually decreases in size, nearly disappearing altogether, a process called involution. Here we show that thymic involution is a highly orchestrated process, coupling degradation of organ architecture to loss of function, and eventually, the decline of peripheral T cell diversity. We established a spatial and single-cell reference of thymus stromal cells, thymocytes and peripheral T cells that integrates organ systems and time.

Last, I will discuss various projects I've worked on and thought about exploring recording cell interactions and time in cells, ranging from direct cell modifications to secreted protein tags.