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Helper T-Cell Subsets and Control of the

Inflammatory Response

Todd N. Eagar, Stephen D. Miller

T cells are key regulators of the inflammatory processes required KEY CONCEPTS
to limit infection. CD4 T cells were initially described as “helper”
cells because of their ability to promote B-cell antibody production. T Cell–Mediated Inflammation Requires Activated
It is now known that CD4 T cells have a much broader influence or Memory T Cells
through regulation of the functions of phagocytes, granulocytes, Naïve T Cells
and other lymphocyte subsets. This is accomplished through • Low frequency
direct cell-to-cell interactions and via the production of cytokines. • Traffic through circulatory and lymphatic systems
The contributions of CD4 T cells to host protection are highlighted • Require professional antigen-presenting cells (APCs) for activation
by the recurrent bacterial, fungal, and viral infections arising in • Require strong costimulation
patients with impaired T-cell responses as a result of genetic • Delayed expansion
diseases (Chapter 35), such as severe combined immunodeficiency • Delayed cytokine production
1
(SCID), or in patients on immunosuppressive therapies. Con- • Dependent on interleukin-7 (IL-7)
versely, dysregulated T-cell responses are associated with rampant Activated T Cells
inflammation and autoimmunity, as seen in patients with such • Traffic through most tissues
conditions as autoimmune lymphoproliferative syndrome (ALPS), • Respond to antigen presented by nonprofessional APCs
autoimmune polyendocrinopathy syndrome type 1 (APS-1) and • Require less costimulation
immune dysfunction, polyendocrinopathy, enteropathy, and • Rapidly expand following antigen encounter
2
X-linked (IPEX) syndrome. Thus a balance must be struck • Rapidly produce effector cytokines
between allowing T-cell inflammation to protect the hosts from • Dependent on IL-2
pathogens and ensuring control mechanisms to prevent injury
from T cell–mediated inflammation. The requisite control is Memory T Cells
established as T cells transit through stages or checkpoints of • Traffic through most tissues
• Dependent on IL-7 and IL-15
the immune response. These include activation, clonal expansion, • Respond to antigen presented by nonprofessional APCs
migration, differentiation, and response termination. • Require less costimulation
• Activation: T-cell function requires antigen-specific T-cell • Rapidly expand following antigen encounter
receptor (TCR) signals and accessory signals. This provides
fine specificity against discrete protein antigens and limits
self-reactivity.
• Clonal expansion: Activated T cells rapidly expand in number
to scale the immune response. of the checkpoints involved in the generation and regulation of
• Migration: T cells traffic through blood, lymphatics, and T-cell biology.
organs. This allows for surveillance and localized effector
responses in diverse tissue types. Activation
• Effector responses: T cells adapt their phenotypes to tailor Activation is required for the naïve T cell to function in effector
the response to the organism and infected tissue. Long-term or memory roles (Fig. 16.1). Full activation requires the cell to
memory cells provide protection from reexposure to the same receive and integrate signals from a minimum of three diverse
pathogens. types of receptors; TCR (signal 1), costimulatory receptors (signal
3
• Termination: T-cell responses are limited through inhibitory 2), and cytokines (signal 3). TCR signals are essential for T-cell
receptors, cell death pathways, and suppression. activation. Each TCR is generated through the process of somatic
T cells are generated in the thymus from lymphocyte progenitor recombination to recognize major histocompatibility complex
cells (Chapter 8). Mature T cells enter the peripheral immune (MHC) and peptide complexes (Chapter 4). Engagement of
system as inexperienced or naïve cells that are incapable of cognate MHC–peptide complex by the TCR activates biochemical
carrying out effector immune responses. To participate in inflam- signals that lead to changes in transcription and ultimately to
mation, T cells must go through an instructional process through T-cell function (Chapter 12). Costimulation and cytokine signals
defined checkpoints. This chapter will discuss the functional can augment TCR signals by amplifying TCR-induced signal
heterogeneity within the CD4 T-cell compartment in the context pathways or by eliciting additional signaling cascades. Activation

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