Page 40 - Clinical Immunology_ Principles and Practice ( PDFDrive )

26 Part one Principles of Immune Response

are T cells. The preponderant lymphocytes in these locations node homing and proliferation, but later stage cells home to the
are B cells (60–70%). 25 periphery, are effector cells, and do not proliferate. 30
Th cells mature in response to foreign antigens. Their function
T Lymphocytes is dependent on the production of cytokine patterns, which
31
T lymphocytes arise from lymphocyte progenitors in bone marrow characterize them as Th type 1 (Th1), Th2, or Th17. The precur-
committed to the T-cell lineage before moving to the thymus. sor Th cell first differentiates into a Th0 cell, which produces
In the early stages of embryogenesis, T-cell precursors migrate IFN-γ and IL-4. The cytokine environment subsequently
26
to the thymus in waves. Associated with this migration is the determines whether Th1 or Th2 cells predominate. Th1 cells
developing ability of thymic education elements, epithelial cells, produce primarily IFN-γ, IL-2, and TNF-α and are important
and DCs to select appropriate T cells. 27 in cell-mediated immunity to intracellular pathogens, such as
In the thymus, T cells rearrange their specific antigen receptors the tubercle bacillus. Th1 cells primarily use T-bet transcription
(TCRs) (Chapter 4) and then express CD3 along with the TCRs factor. Th2 cells produce predominantly IL-4, -5, -6, -10, and
on their surface (Chapter 8). Resting T cells in blood typically -13, as well as IL-2; they predominate in immediate or allergic
range from 7–10 µm in diameter and are agranular, except for type 1 hypersensitivity and primarily use GATA-3 transcription
the presence of a structure termed Gall body, which is not found factor. Other populations of CD4 T cells can develop and rely
in B cells (see Table 2.4). The Gall body is a cluster of primary on IL-23 or IL-12 action upon the cells. If T cells are exposed
lysosomes associated with a lipid droplet. A minority of T cells to IFN-γ, they upregulate both IL-12R and IL-23R, which then
in blood (about 20%) are of the large granular type, that is, they produce either conventional Th1 cells or another subset, Th17,
are 10–12 µm in diameter and contain primarily lysosomes that which produces IL-17 and is important for controlling immune
are dispersed in the cytoplasm. Golgi apparati also are found. cell activation in the gastrointestinal (GI) tract. Overactive
The preponderant form of the TCR, found on about 95% of function of this subset has been associated with autoimmunity.
+
28
circulating T cells, expresses TCRαβ. Some CD3 cells do not The Th17 population preferentially uses RORγt transcription
express either CD4 or CD8 (double-negative, or DN) and express factor. T follicular helper cells are those classically determined
+
an alternative TCRγδ. Further differentiation in the thymus occurs to help B cell responses in germinal centers. They are CD4 ,
+
+
+
from CD3 cells that express both CD4 and CD8 (double-positive, ICOS , and PD-1 ; and they express transcription factor BCL-6.
or DP) to cells expressing either CD4 or CD8 but not both It is likely that there are other epigenetically altered T cells that
(Chapter 8). These mature cells then circulate in peripheral blood allow diversity of function during an immune response.
+
at a ratio of about 2 : 1 (CD4:CD8) and populate lymph nodes, A minor subpopulation (<5%) of CD3 cells in peripheral
the spleen, and other secondary lymphoid tissues. blood express γδ TCR molecules. Most of these cells do not
+
T-cell progenitors, which are CD7 , arise in bone marrow express CD4 or CD8. However, some intraepithelial lymphocytes
from a multipotential lymphoid stem cell. After migration to (IELs) that express γδ TCR also express CD8 αα homodimers
+
the thymus, the CD7 progenitors give rise to a population of in place of conventional CD8 αβ heterodimers. These cells, which
−
+
−
−
CD34 , CD3 , CD4 , and CD8 T-cell precursors, which undergo are thymus independent, are involved in the initial response to
further differentiation into mature T cells. Cytokines produced bacterial antigens presented in mucosal epithelium.
by thymic epithelial cells (e.g., IL-1 and soluble CD23) promote Another minor subpopulation of T cells, natural killer T cells
+
+
+
+
differentiation into CD2 , CD3 thymocytes (see Table 2.3). IL-7 (NKT cells), can be CD4 or CD8 and express a single Vα chain,
−
+
−
induces the proliferation of CD3 DN (CD4 CD8 ) thymocytes, Vα24, which recognizes glycolipids in the context of CD1a, rather
even in the absence of comitogenic stimulation. IL-7 is an absolute than a classic MHC molecule. 31,32 NKT cells express MIP-1 α
requirement for human T-cell development. 29 and β and have a Th1 bias, but lack IL-10 production. The final
IL-2 and IL-4 demonstrate complex effects on thymocyte subset comprises regulatory T cells (Tregs), which occur naturally
+
development. Both can promote development of prothymocytes, and can be induced in vitro. They are CD4 and express high
as well antagonizing their development. IL-6 acts as a costimulator levels of CD25 and the transcription factor FOXP3 and perhaps
33
of IL-1– or IL-2–induced proliferation of DN thymocytes and GARP. These cells are important in regulatory immune responses.
can stimulate the proliferation of mature, cortisone-resistant Tregs are reduced in autoimmunity and in adipose tissue during
thymocytes alone. obesity and increased in cancer.
Subpopulations of T Cells B Cells and Plasma Cells
T cells can be divided into subsets based on surface expression of B cells represent 5–10% of lymphocytes in blood (see Table 2.4).
CD4 and CD8 as well as by function in immune response. CD4 They are typically 7–10 µm in diameter and lack Gall bodies
and CD8 T cells were originally characterized by expression of and granules. The cytoplasm is characterized by scattered
the respective antigen and association with functional ability. For ribosomes and isolated rough endoplasmic reticulum (RER).
example, human T cells expressing CD4 provide help for antibody Unless the cells are activated, the Golgi apparatus is not prominent.
synthesis, whereas cells expressing CD8 develop into cytotoxic B cells express cell membrane immunoglobulin (mIg), the
34
T cells. The distinction is better described on the basis of which majority expressing both IgM and IgD. A small minority of B
antigen-presenting molecule is used for TCR interaction. Thus cells express either surface IgG or IgA. Cell surface molecules
CD4 T cells recognize antigen in the context of MHC class II found on B cells (Chapter 7) include CD19, CD20, CD23, CD40,
molecules, and CD8 T cells recognize antigen presented by class I CD72, CD79a and b, MHC class II, FcγRII (CD32), and comple-
molecules (Chapters 5 and 6). Memory T cells are divided on the ment receptors C3b (CR1a; CD35) and C3d (CR2a; CD21). B-cell
basis of expression of CD45R0, CCR7, CD28, and CD95, which mIg is a part of a B-cell receptor complex that consists of CD19,
categorize the functions of cells as stem cell memory, central CD21, and CD81 (Chapter 4). B-cell proliferation and differentia-
memory, transitional memory, effector memory, and terminal tion processes take place in the germinal centers of the lymph
effector cells. Early memory T cells have high potential for lymph nodes.