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1182 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1183

via absorption by the CD25 receptor, (3) lyse other immune effector STAT3 abrogates Th17 differentiation (Chap. 80). 79,80 Patients lack Th17
cells via granzyme secretion or CD95-CD95L–mediated cell killing, cells and have an increased susceptibility to infection with the various
(4) modulate the activation state and/or function of APCs and other species of Staphylococcus or Candida. Furthermore, the loss of intestinal
immune effector cells, and/or (5) release suppressor factors, such as commensal bacteria that are essential for the induction of Th17 cells
galectin-1 (a β-galactoside–binding protein that can bind and inhibit through the use of antibiotics can cause depletion in intestinal Th17
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the function of many glycoproteins, including CD7, CD43, and CD45) cells, and might account in part for the increased incidence of gastro-
and fibrinogen- like protein 2 (FGL2; a member of the fibrinogen family intestinal infections with C. albicans or Clostridium difficile observed
that mediates it suppressive effect through binding to low affinity Fcγ in patients subjected to long-term, broad-spectrum antibiotic ther-
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receptors expressed on APCs). Consequently, T REG cells can act directly apy. Because of their capacity to enhance inflammation in an antigen-
against specific target antigens, while activating suppressive functions of specific manner, Th17 cells also have been implicated in the devel-
other types of immune effector cells such as CD4+ and CD8+ cells. opment and/or propagation of several autoimmune disease, such as
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rheumatoid arthritis, systemic lupus erythematosus (SLE), MS,
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Th17 T Cells inflammatory bowel disease, glucocorticoid-resistant asthma, and
Naïve CD4+ T cells also can differentiate into Th17 T cells that play psoriasis. 87
an important role in immune responses to certain extracellular patho-
gens and fungi. These cells produce IL-17 (sometimes referred to as T Cells
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IL-17A) and a closely related cytokine, IL-17F, which can form bio- T follicular helper cells (T cells) constitute another subset of CD4+
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logically active homodimers or heterodimers and induce substantial T cells that regulates the development of antigen-specific B-cell immu-
tissue reactions because of the broad distribution of the IL-17 and nity in the germinal center of secondary lymphoid follicles. T cells
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IL-22 receptors. Principal cytokines involved in the differentiation of express the CXCR5 chemokine receptor, allowing them to home to
naïve blood CD4+ T cells into Th17 cells are IL-23 and IL-1β (see Fig. the CXCL13-rich B-cell zones of lymphoid follicles where they engage
76–3), but a combination of TCR stimulation and the cytokines TGF-β antigen-specific B cells in cognate intercellular interactions, and cell-
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and IL-6 are also required. Prostaglandins, most notably prostaglan- surface proteins such as programmed cell death-1 (PD-1), inducible
din E , can synergize with IL-23 and IL-1β to drive differentiation of T-cell costimulator (iCOS), B- and T-lymphocyte attenuator (BTLA),
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CD4+ T cells into Th17 cells. These cytokines and factors can induce and CD40L, which allow them to form stable contacts with anti-
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activation and/or expression of transcription factors that are distinct gen-primed B cells. Such interactions play a critical role in B-cell dif-
from those used by Th1 or Th2 cells, including the retinoic acid-re- ferentiation into plasma cells or memory B cells in response to antigenic
lated orphan receptor γ (RORγt) and STAT3 (see Fig. 76–3), 69,70 which, stimulation. In addition, T cells secrete cytokines such as IL-4, IFN-γ,
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in turn, can induce expression of IL-17 and IL-17F. 71,72 However, for IL-10, and/or IL-21, which partly overlap with cytokines characteristic
full commitment of precursors to the Th17 lineage, RORγt and STAT3 of other T-effector cells, helping to modify the differentiation fate of B
must act in cooperation with other transcription factors, including lymphocytes (Chap. 75).
RORα, interferon regulatory factor 4 (IRF4), and runt-related transcription T cells also express the cytoplasmic adaptor protein signal
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factor 1 (RUNX1). Th17 cells also express high levels of the IL-23R, lymphocyte activation molecule (SLAM)-associated protein (SAP),
CCR4, CCR6, CXCR4, CD161, and multiple CD49 integrins, but not required for lymphocyte interactions, and the transcription factor B-cell
CCR2, CCR5, or CCR7. 37,73,74 In contrast to Th1 or Th2 cells, Th17 cells lymphoma 6 (BCL-6), required for T cell differentiation. Several lines
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do not elaborate IFN-γ or IL-4, both of which can inhibit expression of evidence suggest that T differentiation is a multistage process, but
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of IL-17. 75 that dendritic cells (DCs) are crucial for CD4+ T cell priming and ini-
Th17 cells play a central role in inflammation and defense against tial acquisition of T cell characteristics, including the induction of
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intestinal bacteria, extracellular pathogens, and fungal infections, BCL-6 expression. The flexibility and plasticity of T cells, which
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mostly via activation of neutrophils. Common pathogens that induce is mostly mediated by chromatin modifications, is underlined by the
mainly Th17 responses include Gram-positive Propionibacterium acnes, expression of a constellation of transcription factors, including BCL-6,
gram-negative Citrobacter, Klebsiella pneumoniae, bacteroides and BATF, STAT3, IRF4, c-Maf, and GATA-3, many of which are expressed
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Borrelia species, and fungi such as Candida albicans. Th17 cells are by other Th effector subsets (see Fig. 76–3).
abundantly found in the intestinal lamina propria, where they are
induced and stimulated by commensal bacteria, maintain epithelial Th9 Cells
integrity, and clear extracellular pathogens. 77 Another helper T-cell subset that has recently emerged are Th9 cells. In
Th17 cells are the principal producers of IL-17 in response to spe- contrast to Th17 cells and T , they are induced by the combination of
REGs
cific immune stimulation, but NK and natural killer T (NKT) cells are TGF-β and IL-4 and regulated by the transcription factors PU.1, STAT6,
also able to produce IL-17. IL-17 is a proinflammatory cytokine that IRF4, and GATA-3. They primarily produce IL-9, IL-10, and IL-21.
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has pleiotropic effects on multiple target cells, resulting in enhanced Functionally, Th9 cells appear to be effector rather than regulatory, and
antigen presentation, antibody production, macrophage activation, they have been implicated in the development of allergic reactions, par-
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cellular extravasation, and neutrophil migration. In addition to ticularly in the lungs. Recent data indicates that Th9 cells in vivo might
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IL-17 and IL-17F, Th17 cells elaborate other proinflammatory factors, be implicated in tumor immunity in melanoma. 93,94
including chemokines (e.g., CXCL8 [IL-8] and CCL20), cytokines
(e.g., IL-6, tumor necrosis factor-α, IL-21, and IL-22), growth factors
(e.g., granulocyte colony-stimulating factor and granulocyte-macro- MEMORY T CELLS
phage colony-stimulating factor), acute phase proteins (e.g., C-reactive Following a successful immune response to antigen including the
protein), and antimicrobial peptides and mucins. 76 exposure to and recognition of antigen, expansion of T-cell subsets and
The importance of Th17 cells in the defense against certain micro- exertion of effector function, both naïve CD4+ and CD8+ T-cells can
organisms is reflected in the rare primary immunodeficiency disorder develop into long-lived memory T cells that provide enhanced protec-
called autosomal dominant hyper-IgE syndrome, in which a mutation in tion from re-exposure to the same or a related pathogen. 95,96 Memory
Kaushansky_chapter 76_p1175-1188.indd 1182 9/17/15 4:01 PM