Page 260 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPTEr 16 Helper T-Cell Subsets and Control of the Inflammatory Response 241

of IL-17 and GM-CSF. IL-17, together with TNF-α, strongly cells may play roles in regulating inflammation in other epithelial
promotes inflammation by inducing the expression of adhesion tissues.
molecules, proinflammatory cytokines (including IL-6, GM-CSF,
granulocyte–colony-stimulating factor [G-CSF]), chemokines,
prostaglandin E2, and matrix metalloproteinases (see Fig. 16.2). KEY CONCEPTS
20
IL-21 regulates B-cell, T-cell, and NK-cell functions. In B cells, Regulation of T-Cell Responses
IL-21 has been found to regulate plasma cell differentiation and
promote IgM and IgG1 antibody production. IL-21 is a T-cell • Cell death pathways
growth factor, and in the presence of TCR signals, IL-21 promotes • Tumor necrosis factor (TNF) family receptors: Fas/FasL, TNF-related
apoptosis inducing ligand (TRAIL), and TNFR1
T-cell activation, proliferation, and survival. It therefore appears • Inhibitory receptor activity
that Th17 cells are important for the recruitment of effector • Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1
cells, including neutrophils and monocytes. (PD-1)
In many ways, Th17 cells are potent cell-mediated effectors. • Inhibition of T-cell receptor (TCR) signaling
Th17 responses are elicited in response to infection with extracel- • Cytokine-mediated regulation
lular bacteria and fungi. In addition, Th17 cells have been • Antiinflammatory cytokine production (interleukin [IL]-10, transforming
identified in patients with atopic dermatitis, Crohn disease, growth factor-β [TGF-β])
psoriasis, and multiple sclerosis. Experimental models demonstrate • Cytokines that promote and inhibit inflammation at different stages
of a response (interferon-γ [IFN-γ], IL-2, IL-27)
that Th17 cells, via the production of GM-CSF and IL-17, are • Regulation of apoptosis (LT, TNF-α)
important mediators of autoimmune diseases, including experi- • Growth factor withdrawal (IL-2, IL-7, IL-15)
21
mental autoimmune encephalomyelitis (EAE). Patients with
impaired IL-17 expression or mutations causing Th17 differentia-
tion experience recurrent infections with Staphylococcus aureus REGULATORY T CELLS
and Candida albicans. Alleles of the IL-23R have been found to
confer protection or susceptibility to Crohn disease and psoriasis. Regulatory T cells (Tregs) possess the ability to suppress or
Clinical trials are underway to examine the effects of disrupting otherwise downregulate the function of other proinflammatory
Th17 immune responses in patients with autoimmune diseases. T cells. Although multiple T-cell subsets may possess regulatory
mAbs to IL12/23 p40, IL23 p19, and IL-17a have been approved T cell activity, our understanding of regulatory function was
for treatment of psoriasis and are being investigated for application greatly enhanced by the discovery of CD25 and FoxP3 as markers
in other conditions. for a regulatory subpopulation of CD4 T cells (Chapter 18).
This discussion focuses on the involvement of two populations
Th9 of peripherally derived Treg phenotypes: adaptive Treg and Tr1
Although Th2 cells have long been known to produce IL-9, cells.
recently, it has been proposed that an IL-9 producing T-cell
subset is a separate lineage. Human Th9 cells have been shown Adaptive Tregs
+
+
+
to produce IL-9 and IL-21. IL-9 is an important growth factor In mice, the majority of CD4 CD25 FoxP3 Tregs (natural
for T cells, mast cells, and hematopoietic stem cells (HSCs). IL-9 Tregs) are thought to develop regulatory ability in the thymus.
functions by preventing apoptosis. The differentiation of naïve Peripherally derived adaptive Tregs are similar in phenotype to
T cells into a Th9 phenotype is thought to be dependent on the natural Tregs in that they express CD4, CD25, CD38, CD62L,
22
presence of IL-4 and TGF-β. Th9 cells express the transcription CD103, and FoxP3. Adaptive Tregs are thought to be generated
factor PU.1, which is thought to repress Th2-associated GATA3 in response to prolonged exposure to antigen and are influenced
and Th1-associated T-bet expression. Similar to Th2 cells, Th9 by antigen presentation by immature DCs, plasmacytoid DCs,
cells are thought to play a role in protection from helminths. In or nonprofessional APCs. Experiments suggest that the presence
addition, Th9 cells play a role in asthma, where they promote of inhibitory cytokines, such as IL-10 and TGF-β, also favors
airway restriction and mucus secretion. Experimental models adaptive Treg differentiation. Similar to natural Tregs, adaptive
also suggest that Th9 cells may contribute to the pathogenesis Tregs are capable of suppressing CD4 and CD8 T-cell responses.
of autoimmune disease. Unlike natural Tregs, adaptive Tregs can function through both
cell contact–dependent interactions and through the secretion
Th22 antiinflammatory cytokines. These cytokines may directly regulate
Although IL-22 was originally described as a Th17 cytokine, effector T cells or may inhibit DC activity. The generation of
research has shown that a distinct CD4 T population expressed adaptive Tregs is of great interest as a cell-based therapy for
IL-22 independently of IL-17. Further work identified IL-22, inflammatory diseases, including autoimmunity. 24
IL-13, and TNF-α-secreting cells in the skin of patients with
3
inflammatory skin disorders. These IL-22–expressing cell popula- Tr1 Cells
tions also express the skin homing receptors CCR10. These cells, Tr1 cells have been defined as a population of CD4 T cells that
labeled Th22 cells, have been subsequently found to differentiate produce IL-10 in response to stimulation. Unlike adaptive Tregs,
23
in the presence of IL-6 and TNF-α. Phenotypically, Th22 cells Tr1 cells do not express FoxP3 and do not necessarily express
express a different gene profile than other Th cell types, suggesting CD25. Tr1 cells are produced in the respiratory tract when antigen
that they are a distinct effector population. They also produce exposure is coupled with IL-10 and TGF-β. Experimentally, Tr1
25
fibroblast growth factors that promote epidermal repair. The cells can be induced by repeated intranasal antigen delivery.
hallmark cytokine IL-22 is a member of the IL-10 family with Respiratory tract infections with Bordetella pertussis have also
26
important functions in regulating skin homeostasis and protection been found to elicit Tr1 cells in vivo. Tr1 cells function by
from infection. Experimental models suggest that IL-22 and Th22 producing IL-10 to block proliferation of naïve T cells, prevent