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CHAPTEr 16 Helper T-Cell Subsets and Control of the Inflammatory Response 237

yield 256 daughter cells, each possessing the same TCR. Through nodes. In addition, the S1P1 inhibitor drug, fingolimod, has
the combined proliferative responses of multiple T-cell clones been recently approved for the treatment of multiple sclerosis.
to the same or different epitopes produced by the same pathogen, Fingolimod is thought to prevent the egress of recently activated
a rapid net increase in pathogen-reactive T cells occurs. T cells from the lymph nodes. Natalizumab, an mAb against the
In the clinical setting, T-cell proliferation is a target for α 4 integrin, is utilized in the treatment of multiple sclerosis and
immunosuppression. Some drugs, such as azathioprine, metho- Crohn disease to prevent the migration of T cells to the CNS
trexate, and mycophenolate mofetil, impair T-cell proliferation and intestines, respectively.
by inhibiting nucleotide synthesis. Cyclophosphamide suppresses
DNA replication by alkylating guanine residues. These agents DIFFERENTIATION OF CD4 TH SUBSETS
are used in the treatment of various autoimmune diseases and
for the prevention of graft loss in transplantation. Naïve T Cells
Naïve T cells are precursors for effector and memory T cell
TRAFFICKING subsets. Phenotypically, naïve T cells are small cells with little
cytoplasm; they express surface markers, such as CD45RA, CCR7,
Following activation, T cells change their migration patterns CD62L, CD127, and CD132. They lack expression of markers
(Chapter 11). T-cell migration relies on the actions of selectins, of previous activation, such as CD25, CD44, CD69, CD45RO,
chemokines (Chapter 10), integrins, and matrix proteases. or HLA-DR. Naïve T cells have low metabolism and are unable
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Together, these permit vessel transmigration into lymphatic tissues to produce proinflammatory cytokines. Naïve T cells migrate
12
or sites of inflammation. The differential trafficking of naïve within the secondary lymphoid organs, where they interact with
and effector T cells results from varied expressions of selectins, DCs. Functionally, naïve T cells are not capable of mediating
chemokine receptors, and integrins. The circulation of naïve T effector immune responses. Naïve T cells are predominant after
cells is restricted to blood, lymph nodes, and lymphatic ducts. birth but decline in percentage after puberty. Because of their
This pattern of movement relies on the expression of chemokine role as precursors for all T-effector subsets, their loss is thought
receptor 7 (CCR7), L-selectin or (CD62L), and LFA-1(α L β 2, to be an important contributor to the immunosenescence seen
integrin, CD11a, CD18). CCR7-expressing T cells follow gradients in older adults.
of CCL21 into T cell–rich areas in the lymph nodes, Peyer patches, Early studies demonstrated that CD4 T-cell clones and cell
and spleen. L-selectin allows rolling on the high endothelial lines would express reproducible patterns of cytokine expression
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venule (HEV). LFA-1 and intercellular adhesion molecule-1 designated T-helper cell-1 (Th1) and T-helper cell-2 (Th2). It
(ICAM-1) permit firm adhesion and extravasation. Migration is now appreciated that CD4 effector T cells can differentiate
to the Peyer patches also requires α 4 β 7 integrin in addition to into many functional phenotypes (see Fig. 16.1). These can be
leukocyte function–associated antigen-1 (LFA-1). T-cell retention grouped into four general categories: (i) those possessing pro-
in and egress from the lymph node are regulated by sphingosine inflammatory effector characteristics, (ii) those possessing regula-
1 phosphate (S1P), a secreted phospholipid. S1P sensitivity is tory or antiinflammatory activities, (iii) those that function to
mediated by sphingosine 1 phosphate receptor 1 (S1P1), a G promote B-cell follicle development, and (iv) those that provide
protein–coupled receptor. Recirculating T cells downregulate long-term memory. Our understanding of the phenotype
S1P1. As a result of low S1P levels in the lymph node, S1P1 diversification process is rapidly expanding. From the T-effector
expression allows exit from the lymph nodes in 12–18 hours differentiation models, we learn of three steps. First, TCR signals
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after entry. 13 lead to activation and elicit the expression of cytokine receptors.
During activation, T cells alter the patterns of homing receptors Second, signals through specific cytokine receptors differentially
to reduce the cell’s ability to migrate within the secondary promote the expression of lineage-specific “master” transcription
lymphatic system while gaining receptors needed for trafficking factors that promote expression of genes associated with a
in the peripheral tissues. Very early in the activation process, T particular T-cell phenotype and suppress the expression of genes
cells downregulate S1P1 and express CD69, which suppresses associated with other T-cell phenotypes. Third, the phenotype
chemotactic migration in response to S1P, shed L-selectin, and specific transcription factors induce epigenetic changes that
express the ligands for E- and P-selectin. Additionally, T cells control gene accessibility and maintain the T-cell phenotype in
downregulate CCR7 expression and express a new set of che- a cell-intrinsic manner.
mokine receptors. Following activation, LFA-1 expression is
markedly increased, and the expression of additional integrin EFFECTOR CELL PHENOTYPES
molecules is also induced. One such integrin, very late antigen-4
(VLA-4), is induced by activation and permits T-cell migration T-effector cells promote inflammation through the release of
into the central nervous system (CNS), lungs, and intestines. 14 cytokines (Fig. 16.2). Cytokine release elicits the activity of
Differential expression of homing receptors between naïve accessory cells, which ultimately mediate the inflammation to
and activated T cells facilitates their diverse functions. Naïve T clear the antigen. The pattern of cytokine production ultimately
cells in the lymphatic tissues are in close proximity to a concen- dictates the type of inflammation (Table 16.1). Effector T cells
trated collection of DCs from many tissues; this facilitates antigen are divided into five basic groups: Th1, Th2, Th9, Th17, and
encounter. The function of activated T cells in immune surveil- Th22. Table 16.2 summarizes responses the T-effector responses
lance, in contrast, is facilitated by migration through diverse associated with selected pathogens.
tissues.
The multistep process of migration and the tissue selectivity Th1
of migration receptors have been targeted for the treatment of Th1 cells are defined by production of the cytokines interferon
autoimmune diseases. Antibodies targeting CD62L and LFA-1 (IFN)-γ, granulocyte macrophage–colony-stimulating factor
have been developed to prevent the entry of T cells into lymph (GM-CSF), IL-2, and lymphotoxin (LT, tumor necrosis factor