Download ANTIGEN PROCESSING AND PRESENTATION

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NATIONAL CHENG KUNG UNIVERSITY MEDICAL COLLEGE
MEDICAL MICROBIOLOGY COURSE
Wednesday, March 2, 2011, 8:10-10:00 a.m.
ANTIGEN PRESENTATION
CELL COOPERATION IN THE ANTIBODY RESPONSE
Yee-Shin Lin, Ph.D.
A. BACKGROUND
T cells recognize peptide fragments which have been processed and presented by MHC molecules on
APC. The MHC class I and class II molecules present peptides derived from endogenous and exogenous
antigens, respectively. CD4 cells recognize antigen plus class II MHC molecules while CD8 cells
recognize antigen plus class I MHC molecules. In addition, intercellular adhesion molecules and
co-stimulatory molecules are involved in T-cell activation.
The humoral immunity can be dependent or independent on T cell function. Most immune responses
require the interaction of several cells, in a specific, sequential manner. Antigen-presenting cells (APCs)
present Ag to helper T (TH) cells, specific activation and maturation signals are delivered by TH to B cells
causing B cells to mature into plasma cells and secrete specific antibody. Mutation of Ig genes, followed
by selection of high-affinity clones is the basis of affinity maturation. These processes occur in germinal
centers. Class switching is effected by somatic recombination occurring within the heavy chain genes.
Reading: Male, Brostoff, Roth & Roitt [chapters 7 and 8]
B. LECTURE SUMMARY
ANTIGEN PRESENTATION
ANTIGEN-PRESENTING CELLS: Several cell types can act as antigen-presenting cells (APCs). [Fig.
7.2, 7.3, 7.4]
ANTIGEN PROCESSING AND PRESENTATION Antigens are processed before they are presented to T cells. The MHC class I molecules present peptides
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derived from endogenous antigens and the MHC class II molecules present peptides derived from
exogenous antigens. [Fig. 7.9, 7.11, 7.13]
Cross-presentation: [Fig. 7.15]
CO­STIMULATORY MOLECULES Intercellular signals in T cell activation involve adhesion, antigen-specific activation, co-stimulation, and
cytokine signaling [Fig. 7.1]. Molecules involved in the interaction between T cells and APCs (in
addition to MHC/Ag/TCR/CD4 or CD8) are shown in Fig. 7.16 (CD28/B7, LFA-1/ICAM-1, CD2/LFA-3,
and various cytokines). CTLA-4, the alternative ligand for B7, is an inhibitory receptor limiting T cell
activation [Fig. 7.17]. A T cell requires signals from both the TCR and CD28 for activation [Fig. 7.18].
The highly ordered area of contact between the T cell and APC is an immunological synapse [Fig. 7.19].
T CELL ACTIVATION: The signaling pathway in T cell activation is shown in Fig. 7.21. T cells can
also be activated by mitogens and superantigens [Fig. 7.22]. T cell activation leads to production of IL-2
and high-affinity IL-2R [Fig. 7.23].
CELL COOPERATION IN THE ANTIBODY RESPONSE
DEVELOPMENT OF B CELLS [Fig. 8.1]
T-DEPENDENT AND T-INDEPENDENT ANTIGENS [Fig. 8.4]
1.
T-dependent antigen: the response to the antigen depends on both T cells and B cells recognizing that
antigen.
2.
T-independent antigen: the antigen is capable of activating B cells to produce antibody independently
of T cell help. They are large polymeric molecules with repeating antigenic determinants [Fig. 8.3].
Induce poor memory and tend to activate CD5+ subset of B cells (B-1 cells) [p. 166].
MECHANISMS OF B-CELL ACTIVATION BY T-DEPENDENT ANTIGENS:
1.
A specific T cell, using TCR, recognizes both the processed Ag and MHC class II molecule on the
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surface of the APCs. [Fig. 8.5]
The resting T and B cells have receptors for IL-1. Both IL-1 and antigen activation via receptors
these two signals lead to the induction of T and B cells. T cells then express receptors for IL-2 and
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3.
start to produce IL-2, T cell growth is thus initiated.
B cells bind Ag via specific cell surface receptors (Ig molecules, remember?). B cells are thus
activated in the presence of IL-1, and are driven to division and differentiation by other cytokines, i.e.,
IL-2 and IFNγ from Th1 cells, and IL-4, IL-5, IL-6, IL-10 and IL-13 from Th2 cells [Fig. 8.9]. The
interaction between T cells and B cells is a two-way process, in which B cells present antigen to T
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cells and receive signals from T cells, for division and differentiation [Fig. 8.5]. The interaction is
augmented by a number of cell surface molecules [Fig. 8.8].
The B cell transforms into a plasma cell (antibody-forming cell, AFC) and secretes Ig.
SIGNALING PATHWAYS IN B-CELL ACTIVATION [Fig. 8.6, 8.7]: Ig and Igα/Igβ complex,
co-receptor complex (CD21, CD19, CD81)
ACTIVATION AND DIFFERENTIATION OF B CELLS IN GERMINAL CENTER: clonal
proliferation, somatic hypermutation, receptor editing, isotype switching, affinity maturation, and
selection by antigen. [Fig. 8.12, 8.13]
ANTIBODY RESPONSES IN VIVO
1.
Four phases of a primary antibody response: [Fig. 8.15]
a.
b.
c.
d.
2.
lag phase
log phase
plateau phase
decline phase
Comparison of primary and secondary antibody responses [Fig. 8.16]
Time course
Ab titer
Ab class
Ab affinity
Primary
Secondary
longer lag phase
low
IgM first, then IgG
low
shorter lag phase
high
IgG
high (affinity maturation)
DIFFERENTIATION OF B CELLS
Affinity maturation: The antibodies produced in a secondary response (to a T-dependent antigen) have
higher average affinity than those produced in the primary response. The affinity maturation involves:
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a.
b.
The selective expansion of clones of high affinity antibody producing cells which is associated with
the switch from IgM to IgG production.
The antigen dose administered that high antigen doses produce a lower affinity response than low
antigen doses. [Fig. 8.17]
Class switching [Fig. 8.18-8.22, 8.25]
The first B cells to appear during development carry surface IgM as their antigen receptor. Upon
activation, other classes of Ig are seen, each associated with different effector functions. During class
switching, all that changes is the constant region of the heavy chain. The expressed V(D)J region and
light chain do not change. Antigen specificity is therefore retained.
C.
ImmunObjectives -- a self assessment
1.
Define:
z APCs
z Cross-presentation
z CD28 and CTLA-4
z ITAM and ITIM
z immunological synapse
z superantigen and mitogen
z IL-2R
z primary/secondary antibody responses
z T-dependent/T-independent antigens
z affinity maturation
z class switching
2. How are endogenous and exogenous antigens processed and presented by MHC class I and class II
molecules, respectively?
3. What are the molecules involved in the interaction between T cells and APCs? (including adhesion,
antigen-specific activation, co-stimulation, and cytokine signaling)
4.
Describe the signaling pathways of T cell activation.
5. Familiarize yourself with the signal pathways in B-cell activation (receptors, co-receptors,
intracellular signals).
6.
Familiarize yourself with various steps involved in a T-dependent immune response.
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7.
Know B-cell development in germinal centers.
8. How can different isotypes of Ig be generated which are directed against the same determinant (have
the same antigenic specificity)?