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CHAPTEr 16 Helper T-Cell Subsets and Control of the Inflammatory Response 243

phenotypes are maintained through active signaling and chro- TERMINATION OF T-CELL RESPONSES
mosomal modification.
Third, polarization is incomplete at the population level.
Following exposure to antigen, responding T cells may collectively CLINICAL rELEVANCE
possess multiple phenotypes. Heterogeneity of Th phenotypes Diseases Associated With CD4
is a common feature of some diseases, such as asthma, where T-Effector Responses
Th2, Th9, and Th17 responses are thought to contribute to disease;
in psoriasis, where Th1, Th17, and Th22 cell types are detectable; Th1
and in multiple sclerosis, where Th1, Th17, and Th22 cells are • Multiple sclerosis
thought to mediate inflammation. A portion of the T cells may • Psoriasis
• Type 1 diabetes mellitus
persist in a naïve phenotype or as uncommitted T cm or T scm that • Tuberculoid leprosy
may give rise to T cells of a different phenotype upon antigen • Transplant rejection
reexposure.
Fourth, there is limited plasticity in T-cell effector phenotypes. Th2
Effector phenotypes are reinforced by “master” transcription • Allergy and asthma
factors and epigenetic modifications (Fig. 16.4). For example, • Helminthic infections
established Th1 cells do not express Th2 cytokines despite • Lepromatous leprosy
extended culture in Th2-skewing conditions. There is, however, Th9
growing evidence of interconversion between certain T-helper • Asthma
32
subsets. Experiments tracing T-cell lineage commitment have • Helminthic infections
shown that T cells that once expressed FoxP3 could become
effector cells. It is not clear if plasticity is occurs between all Th17
phenotypes or if phenotype conversion can occur at any stages • Asthma
of phenotype commitment (see Fig. 16.4). • Multiple sclerosis
• Psoriasis
• Rheumatoid arthritis
• Transplant rejection
Primary stimulation Secondary stimulation
Th22
T h9 T h9 • Psoriasis
• Wound healing
T h22 T h22

DC As a result of the potential for unregulated inflammation, retention
+ of activated effector T cells present three risks to the organism.
T h1 T h1 First, with each succeeding infection, the body would be increas-
ingly burdened by the energy requirements of maintaining larger
DC T h2 T h2 T-cell numbers. Second, there would be loss of TCR diversity
Tcell

T h17 T h17 resulting from the overrepresentation of clonally expanded
T cells. Third, there is an increased risk of damage to self by
T cm T h1 large populations of activated effector T cells. Thus a return to
homeostasis is required at the end of an immune response through
T h2 reductions in T-cell numbers and activity. Homeostasis is restored
through the loss of the initiating stimulus and by active control
T h17 processes, including cell death, inhibitory signaling pathways,
and antiinflammatory cytokines.
T cm
T h9 CELL DEATH PATHWAYS IN T-CELL HOMEOSTASIS
T h22 Several cell death pathways regulate the processes of activation-
induced cell death (AICD; Chapter 13). The primary pathway
FIG 16.4 Mechanism of T-Helper (Th) Phenotype Shift. Under involved in AICD involve Fas (CD95) and Fas ligand (FasL,
appropriate conditions, T-cell activation may result in daughter CD95L). Fas and FasL are expressed following T-cell activation.
cells adopting one of several T-effector phenotypes. Within a Fas-mediated apoptosis can be stimulated by FasL on neighboring
polarized population of Th cells, a subset of undifferentiated T cells (“death signal”) or on the same cell (“suicide signal”).
lymphocytes may exist (here referred to in the general category Mutations in Fas and FasL result in the accumulation of activated
as T central memory [T cm]). Fully committed Th1, Th2, or Th17 lymphocytes and autoimmunity. Another TNF family member,
cells upon restimulation will produce Th1, Th2, or Th17, respec- TNF-related apoptosis inducing ligand (TRAIL), has also been
tively. T cm or other uncommitted cell types retain the potential associated with AICD. Mice lacking TRAIL have enhanced
to differentiate into T effectors of any phenotype, depending susceptibility to autoimmune disease. Some evidence suggests
on the context of the secondary stimulation. that TRAIL regulates AICD primarily in Th2 cells. 33