CHAPTER 14 The Adaptive Immune Response in Space and Time

T cell interacting with fibroblastic reticular cell network. A T cell (cyan) interacts closely with the FRC network (stained red and green) as it scans the surface of dendritic cells whose processes are also associated with the network (not shown).

Learning Objectives

After reading this chapter, you should be able to:

1. Visualize the behavior of innate and adaptive immune cells before, during, and after a response to antigen in living tissue; recognize the role dynamic imaging approaches have played experimentally.
2. Outline the events that lead to activation and differentiation of APCs, CD4⁺ T cells, CD8⁺ T cells, and B cells.
3. Provide examples of the behavior of effector lymphocytes in peripheral tissues.
4. Identify the multiple variables that influence immune cell movement, positioning, and localization.

Key Terms

• Dynamic imaging
• Selectins
• Adhesion molecules
• Addressin
• Extravasation
• Diapedesis
• Sphingosine 1-phosphate (S1P)
• Homing receptors
• Chemokines
• Chemokine receptors
• Subcapsular sinus (SCS)
• B-cell follicle
• Germinal center
• T-cell zone
• Paracortex
• Periarteriolar lymphoid sheath (PALS)
• Marginal zone
• Fibroblastic reticular cell (FRC)
• Follicular dendritic cell (FDC)

Imagine trying to understand American or European football simply from snapshots taken of players. You could certainly learn something about how the games are played, particularly if you carefully noted differences in the color of jerseys, the directions players are facing in snapshots, implied motion of feet relative to the position of a ball, and contact between players. Imagine then having the capacity to pull one or two players off the field and examine them, with and without a ball. This would add to your understanding. However, you may still miss the relevance of each position on the team, the significance of substitutions, and the rationale behind a stop in play. You are even more likely to misinterpret the antics of players who have just sacked a quarterback or flopped in dramatic agony in front of the goal. Now imagine that you can watch and listen not just to one entire game, but to many games, in real time. With that luxury, you have a real chance of understanding the rules behind, and meanings of, each activity.

Understanding the rules governing cell activities during an immune response is even more daunting. Immune cells are the most mobile, dynamic cells in the body. They browse every tissue, and organize responses in nearly every niche. They are also among the most diverse collection of cells that form a tissue, and their individual phenotypes and functions change over the course of the immune response. Immune cell choreography, indeed, can seem impenetrable. However, some of the most elegant cellular, molecular genetic, and biochemical experiments in biology have successfully revealed many of the rules behind the movements of immune cells in space and time. New technologies that allow us to trace the dynamic behavior of individual cells in living organisms have ushered in a new experimental era that is filling gaps in our understanding of the immune response.

Dynamic imaging techniques, including two-photon (2P) intravital fluorescence microscopy (see Chapter 20), allow investigators to directly visualize immune cells responding to antigen in living organisms. Single-cell transcriptome sequencing allows investigators to follow changes in gene expression of thousands of individual cells over the course of an infection. Teams of immunologists, geneticists, biophysicists, biochemists, and computer scientists continue to develop other innovative approaches that bring us ever closer to the ability to visualize and interpret the complex choreography of an immune response in its physiologic context.

This chapter takes advantage of these recent advances to cap our exploration into the basic immunology of an immune response by offering glimpses of immune cells in the tissues where they reside. Because foundational investigations first mapped the behavior of lymphocytes, we focus largely on the adaptive immune response. Investigations into innate immune cell behavior have also begun to yield intriguing results; stay tuned for future updates and insights.

We start with a general summary of the dynamic behavior of innate and adaptive immune cells in healthy tissue (in homeostasis). We then summarize what we know about the behavior of the innate and adaptive immune cells when they first encounter antigen. First, we examine the behavior of innate immune cells in tissues that have been breached by antigen, and then we discuss the choreography of innate and adaptive cells during the induction of a primary response in secondary lymphoid tissues. We focus primarily on the behavior of cells during the adaptive immune response in lymph nodes, the secondary lymphoid organ that has been most accessible to imaging techniques. We then address the activity of mature effector and memory lymphocytes that emerge from the primary immune response, describing current examples of the in vivo behavior of cells as they actively respond to infection or transplantation.

Because the regulation of cell movement is so important in studies of immune cell dynamics in living tissue, we also include an Advances box that describes the molecular basis for cell trafficking in more detail. It can be used as a springboard to explore and understand more advanced literature.