|Week #||Topics||lecture summaries|
|2||Immune Responses to Cancer||
Tumors form aberrant tissues that can be aided or destroyed by the immune system. While the study of the immune system’s response to tumor growth has a long history, it is only in the past 20 years that the cellular players and precise mechanisms enabling immune repression of tumor growth have been identified.
Shankaran and colleagues (2001) studied mice lacking a functional immune system and tested their propensity to develop tumors. This study helped open the field to the main models and concepts that are used to study tumor immunology, and led to the important notion of immunoediting.
Moving from mice to humans, Galon et al. (2005) examined tumor biopsies from colorectal cancer patients. The authors quantified tumor inflammation by quantifying T cell presence within the tumor, which demonstrated the clear link between tumor infiltration by T cells and patient outcomes over several years.
|3||The Physical Basis of Cell Motility I||
This week we will move from immune systems to the protein networks that drive the motility of many cell types —immune and nonimmune— conserved across many species. The proteins of the cytoskeleton confer mechanical properties to cells and are the basis of cell shape change as well as motility.
One of the foundational discoveries of actin filaments is described in the first paper by Julie Theriot and Tim Mitchison (1991). Many years later, new genetic and microscopy tools permit fluorescence speckle microscopy, by which the motions and associations of individual proteins can be resolved.
Ponti et al. (2004) leverage this technique to derive quantitative descriptions of the polymerization and dissolution of actin filaments that power cell movement. These dynamics emerge from actin polymerization and myosin motors that deform and contract actin filaments, together yielding a contractile filament network inside cells.
|4||The Physical Basis of Cell Motility II||
We continue our discussion of cytoskeletal dynamics that condition cell movements. Cells must integrate the biochemical cues that drive cytoskeleton assembly and breakdown to drive translocation in a single direction. What biochemical signal or physical condition sets these cues into motion?
Houk and colleagues (2012) consider how cells form and maintain a “front” and a “rear” as they migrate. Their work incorporates physical, biochemical, and modeling evidence to conclude that tension of the cell membrane serves to reinforce the “front” and maintain cell polarity.
The second paper addresses how cells link the dynamics of actin filaments with their environment using special adhesion receptors called integrins. Along with the molecular motor myosin, actin and integrins permit cells to do much of the movement that we will consider for the remainder of the course. Integrins will become important later in the course for their unique roles in immune cells. This week we will discuss integrin-based adhesions as they are known in non-immune cells to grasp their fundamental functions as described by Aratyn-Schaus and Gardel (2010).
|5||Specialized Adhesions Formed by Immune Cells||
This week we begin to integrate the topics of cell migration and immune cell function. One of the earlier reports that take up this link is by Dustin and colleagues (1997). This work accomplished a conceptual advance in observing T cells on a surface patterned with antigen-bearing receptor complexes that trigger T cell receptor activation. Like nonimmune cells, dendritic cells, the immune system’s sentinels, use integrins to adhere to their surroundings. Yet dendritic cells must adhere to another substrate: other cells.
We will expand our consideration of integrin-based adhesions to alphaE integrin, also known as CD103, which permits immune cells to adhere to a protein found on many epithelial cells. The report by Schlickum et al. (2008) describes this unique integrin and its function on dendritic cells.
|6||Modes of Cell Migration in and out of Confinement||
Cell migration has been described in great detail for non-immune cells adhering to a solid substrate, but immune cells do not exhibit efficient migration in this context. Rather, immune cells use the close confinement of their normal surroundings – tissues or interstitial spaces – to move quickly.
The first paper for this week, by Friedl and colleagues (1998), is an early report about the mechanisms of immune cell migration, observing that immune cells can move quickly without forming canonical adhesions to their surroundings. This unique mode of migration is not as specialized as it might seem, however, as concluded by Liu et al. (2015). The confinement that permits immune cells to move so efficiently induces changes in the cellular cytoskeleton that are independent of cell type. This observation led to a reconsideration of the “special” case of immune cell migration and prompted a new understanding of cell locomotion based on the actin cytoskeleton.
|7||Guest Lecture: Jeff Kuhn, Director of the Microscopy Core Facility at the Koch Institute||
No Lecture Summary
|8||Signals that Guide Immune Cell Motility||
The immune system must be poised to place many cells of a given type into an area very quickly —whether to combat an invading pathogen or to find and activate a specific T cell clone. The ability of immune cells to rapidly congregate is frequently controlled by guidance cues that impinge on the motility machinery we have previously discussed to coerce migration to the right place.
First we will take a broad look at chemotaxis by an amoeba that migrates toward a diffuse, soluble gradient. Tweedy and colleagues (2020) examine the slime mold Dictyostelium, a simple organism capable of complex migration feats. The ability of these humble cells to navigate complex environments highlights the power of chemotaxis conserved across taxa.
Next we consider haptotaxis, which is migration along a solid-phase (rather than freely diffusing) gradient. Schumann et al. (2010) take a close look at the chemokine CCL21, which dendritic cells use to find their way to lymph nodes. Their work established quantitative estimates for CCL21 density and its effects on dendritic cell migratory behaviors.
|9||Integrating Start and Stop Signals in Immune Cells||
Looking beyond the simple components of cell migration machinery, we will now put these together with the biological roles of immune cells to see how migration is controlled to execute immune cell functions. The cues for actin dynamics that drive cell migration have evolved with cell adhesive forces to tune migration.
In our first paper, Hons and colleagues (2018) dissect how actin flow and friction from integrin receptors are optimally coupled in T cells. Dendritic cells also must use different actin dynamics for separate functions, as explored by Vargas et al. (2016). Their observations link subcellular actin architecture with immature vs. mature dendritic cell migration and therefore function.
These pathfinding decisions are addressed by Renkawitz and colleagues (2019), who find that the nucleus determines the cell’s direction as it is the largest organelle inside dendritic cells. The second paper by Gérard et al. (2014) offers a view into the kind of migration that immune cells must execute to locate rare pathogens. This work takes a close look at T cell migration and its tortuosity, as cells meander on their path toward an attractant. The authors place this behavior in an immunological context to derive important conclusions about not just the speed or frequency but also the pathfinding of T cell motility.
|11||Migration in Immune and Nonimmune Tissues||
With a solid grounding concerning immune cell migration, we will move to physiological settings in which immune cells traffic. First we will look carefully at lymph nodes, which are large and complex structures that serve as hubs for many immune cell types. Among many other cell types, T cells and dendritic cells find one another to start adaptive immune responses to pathogens or cancer.
The dense environment of the lymph node makes this a challenging prospect, so Bajénof and colleagues (2006) used live imaging of mouse lymph nodes to observe T cells moving in the lymph node. They uncovered spatial and adhesive guides that corral T cells into the zone where they might find their cognate dendritic cells. Our next paper examines a subset of dendritic cells in tumors with specialized migratory and T cell activation capacities.
These dendritic cells are prognostic for improved patient outcomes and responses to therapy, and Engelhardt et al. (2012) identified and characterized them using a combination of imaging and flow cytometry. Their work also provoked new models for dendritic cell engagement with T cells, a problem that to this day remains incompletely resolved.
|12||Cytoskeletal Regulation of Immune Cell Functions||
The actin cytoskeleton in immune cells does more than control and orient their migration. The functions of immune cells that confer their primary roles in immune defense have coevolved with the mechanical properties of the actin cytoskeleton. Adhering to another cell and organizing receptor-ligand interactions both require the dynamic structures formed by actin and myosin to unfold properly. This week we zoom in on two subcellular processes and consider their tight control by the cytoskeleton.
First, Comrie and colleagues (2015) find that the cytoskeleton of dendritic cells must hold a critical adhesion receptor immobilized on their surface during T cell engagement. This receptor must resist the motions of its cognate ligand on the apposed T cell, or risk failure of T cell activation.
Our second paper examines another cell-cell engagement, this time between a T cell and the target cell it targets for destruction. Basu et al. (2016) find that forces exerted within the plane of the T cell–target cell contact are critical for efficient cell killing. Their work integrates direct mechanical measurements that serve as important benchmarks for understanding forces that direct biological outcomes.
|13||Oral Presentations and Wrap-Up||
In our last session, we will hear oral presentations from all students and critique their selected journal articles together. We conclude the course by sharing parting thoughts and feedback to the instructor on what went well and what could be improved, in addition to completing written course evaluations.