CHAPTER 10 T-Cell Activation, Helper Subset Differentiation, and Memory

Dendritic cells (blue-green) interacting with a T cell (pink).

Learning Objectives

After reading this chapter, you should be able to:

1. Describe the two main signals needed to activate a naïve T cell and the difference between costimulatory and coinhibitory signals.
2. Describe the extracellular influences (polarizing cytokines) and intracellular influences (master gene regulators) that drive differentiation of naïve CD4⁺ T cells into helper T-cell lineages, as well as what distinguishes the various lineages functionally (effector cytokines).
3. Outline the major differences between type 1 and type 2 immune responses and understand how distinct helper T-cell subsets contribute to these responses.
4. Identify the four main memory T-cell subsets, understand their functions, and speculate about their origin.
5. Recognize some of the questions that still remain as we work to understand T-cell activation, differentiation, and memory.

Key Terms

• Naïve
• Two-signal hypothesis
• Avidity
• Anergy
• Costimulatory receptors
• Coinhibitory receptors
• CD28
• Programmed cell death protein-1 (PD-1 or CD279)
• Polarizing cytokines
• Type 1 responses
• Type 2 responses
• Adjuvants
• Master gene regulator
• Effector cytokines
• T helper type 1 (T_H1) cells
• T helper type 2 (T_H2) cells
• T helper type 17 (T_H17) cells
• Peripheral T_REG (pT_REG) cells
• T follicular helper (T_FH) cells
• T helper type 9 (T_H9) cells
• Central memory T cells (T_CM)
• Effector memory T cells (T_EM)
• Resident memory T cells (T_RM)
• Stem cell memory T cells (T_SCM)

The interaction between a naïve T cell and an antigen-presenting cell (APC) is the initiating event of the adaptive immune response. Prior to this, the innate immune system was alerted to infection or tissue damage, and antigen-presenting cells were activated via pattern recognition receptors. These APCs may have engulfed extracellular (or opsonized intracellular) pathogens, or they may have been infected with an intracellular pathogen. In either case, they have processed and presented peptides from these pathogens in complex with surface MHC class I and class II molecules, and migrated to secondary lymphoid tissue, including local (draining) lymph nodes, Peyer’s patches (see Chapter 13), and/or the spleen. Within these secondary lymphoid tissues APCs settled in the T-cell zones, joining networks of resident APCs, to be continually scanned by roving naïve CD8⁺ and CD4⁺ T cells, which recognize MHC class I–peptide and MHC class II–peptide complexes, respectively. (Chapter 14 provides an overview of the initiation of an immune response in secondary lymphoid tissue.)

We have seen that each mature T cell expresses a unique antigen receptor assembled via random gene rearrangement (Chapter 6) during T-cell development in the thymus. Positive and negative selection in the thymus ensures that the mature, naïve T cells that enter the circulation are largely tolerant to self antigens, and restricted to self MHC (Chapter 8). Some naïve T cells commit to the CD8⁺ cytotoxic T-cell lineage, others to the CD4⁺ helper T-cell lineage. If, during their migration through secondary lymphoid organs, naïve CD8⁺ or CD4⁺ T cells bind tightly to an MHC-peptide complex expressed by an activated dendritic cell, they become activated by signals generated through their T-cell receptors (TCRs). As we will learn in this chapter, TCR signals in concert with costimulatory and cytokine signals stimulate naïve T cells to proliferate and differentiate into effector T cells.

In this chapter, we specifically review the cellular and molecular events that activate naïve T cells and investigate the variety of costimulatory interactions that play an important role in determining the outcome of T cell–APC interactions. We then discuss the end result of naïve T-cell activation—the development of distinct effector and memory T-cell subsets—focusing primarily on the various fates and functions of the CD4⁺ helper T-cell (T_H) lineages that drive both B- and T-cell adaptive responses (Overview Figure 10-1). As you know, naïve CD8⁺ T cells differentiate into cytotoxic cells in response to engagement of MHC class I–peptide combinations. Although we describe the initial activation and differentiation of CD8⁺ T cells in this chapter, we spend more time on their cytotoxic effector functions in Chapter 12.

OVERVIEW FIGURE 10-1

T-Cell Activation and Differentiation

Activation of a naïve T cell in the secondary lymphoid tissues results in the generation of effector and memory T cells. Activation requires several receptor-ligand interactions between the T cell and a dendritic cell, as well as signals through cytokines produced by the activating APC as well as other supportive cells in the lymphoid organ. CD4⁺ T cells become effector helper T cells (T_H) and secrete cytokines that enhance the activity of many other immune cells. CD8⁺ T cells become cytotoxic T cells (T_C) that kill infected cells.

The events occurring in the lymphoid organs are enlarged from the immune response scheme diagram. It shows the different phases of T-cell activation and differentiation. In the antigen recognition phase, a na�ve CD4 superscript plus T cell and a na�ve CD8 superscript plus T cell bind to an APC via receptors and coreceptors. The IL-2 cytokine binds to the IL-2R receptors of the T cells. The costimulatory and cytokine signals stimulate activation of the T cells. Clonal expansion follows activation. The CD4 superscript plus T cell and the CD8 superscript plus T cell interact with the cytokines from the activation stage and from other cellular sources, and multiply in number. T-cell differentiation follows clonal expansion and the T cells migrate to peripheral tissues. The CD4 superscript plus T cells differentiate into helper T cells (T subscript H) such as effector CD4 superscript plus T cells and memory CD4 superscript plus T cells. The memory CD4 superscript plus T cells can also give rise to effector CD4 superscript plus T cells. The CD8 superscript plus T cells differentiate into cytotoxic T cells (T subscript C) such as effector CD8 superscript plus T cells (CTL) and memory CD8 superscript plus T cells. The memory CD8 superscript plus T cells can also give rise to effector CD8 superscript plus T cells. Helper T cells induce activation of macrophages, B cells, and other cells. Cytotoxic T cells are involved in the killing of infected �target cells� and macrophage activation.

Here, we explore the surprising number of helper lineages that a naïve CD4⁺ T cell can adopt (T_H1, T_H2, T_H17, T_FH, pT_REG, T_H9, and more), and broadly discuss their functions. We also examine what regulates a CD4⁺ T cell’s lineage decision, and how it is influenced by the response of the innate immune system to specific pathogens and antigens. We close the chapter with a discussion of the generation of T-cell memory, introducing the multiple memory subsets and current thinking about their origin and function.

A Classic Experiment box describes the basic research behind the discovery of the costimulatory molecule CD28, an essential participant in naïve T-cell activation. The first Clinical Focus box describes the development of an exciting new immunotherapy for cancer that took advantage of the discovery of a relative of CD28 that inhibited rather than enhanced T-cell activation. Together, these boxes illustrate the powerful connection between basic research and clinical advances. This partnership is the basis for translational research, an effort to bring the bench to the “bedside” that has captured the imagination of many biomedical investigators and clinicians.

The Advances box describes recent insights into the origin of regulatory T cells that play a role in maintaining maternal-fetal tolerance during pregnancy. The second Clinical Focus box discusses how a disease, an “experiment of nature,” has helped us to better understand the basic biology and physiological function of one of the helper cell subsets (T_H17) introduced in this chapter.