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Cell-Mediated Immune Responses
Cell-Mediated Immune Responses
PHYSIOLOGY OF IMMUNITY
•involves the following series of events that culminate in B cell or T cell activation (or both ) and response
to the introduction of a foreign into the circulation :
•processing of the foreign entity by a macrophage or B cell
•recognition of this foreign entity by specific , preformed receptors on certain B cells and T cells
•proliferation of these B cells and T cells , as stimulated by soluble signals(interleukins ) between
macrophages , B cells and T cells
•blast transformation and a series of mitotic divisions leading to the generation (from B cells ) of plasma
cells that produce immunoglobulins and ( from T cells ) of sensitized T cells – all capable of interacting with
the original foreign stimulus
T-dependent antigens
are proteins; they stimulate all
five classes of immunoglobulins
and can elicit an anamnestic
(secondary-booster) response
T-independent antigens
T cells
-mature in the thymus
-are involved in “helping”B cells become antibody-producing plasma cells
-have specific receptors (T cell receptors) on their surface for antigen recognition
-are involved in cell mediated immunity
-participate in suppresion of the immune response
-are the predominant 95% lymphocytes in the circulation
-are found in the paracortical and interffolicular areas of the lymph nodes and spleen
The morphology of lymph nodes. A, This
schematic diagram shows the structural
organization and blood flow in a lymph node. B,
This light micrograph shows a cross section of a
lymph node with numerous follicles in the cortex,
some of which contain lightly stained central
areas (germinal centers), and the central medulla.
CD (cluster of differentiation) markers
•arise on T cells during maturation in the thymus
•appear on T cells in the following sequence:CD2(T11); CD3(T3); CD4(T4); CD8(T8)
CD2
•is the earliest T cell marker
•is the sheep red blood cell (SRBC) receptor
•is present on virtually every peripheral T cell
CD3
•is intimately associated with TCR
CD4
•is present mainly on helper T cells
•is involved in interaction with class II human leukocyte antigens (HLAs)
CD8
•is present mainly on cytotoxic T cells
•recognizes class I HLAs
Ontogeny of T cells
•occurs as stem cells flow through the thymic cortex , into the medulla and then out into the general
circulation
•begins in the thymic cortex with the appearance of CD2 , followed by appearance of CD3 (with TCR), then
with concomitant expression of CD4 and CD8
•in the thymic medulla consists of a loss of marker to produce two populations of cells – one CD2+
,CD3+,TCR+, CD4+ (65%); and the other CD2+ ,CD3+,TCR+, CD8+ (35%)-that are then released into the
peripheral circulation
•is the time when both positive selection and negative selection occur
•To perform these functions, the naive T cells have to differentiate into
effector cells, process is initiated by antigen recognition
•The protein antigens of microbes are transported from the portals of entry
of the microbes to the same peripheral lymphoid organs through which naive
T cells recirculate
•In these organs, the antigens are processed and displayed by MHC molecules
on dendritic cells, the antigen-presenting cells (APCs) that are the most
efficient stimulators of naive T cells
•At the same time as the T cells are seeing antigen, they receive additional
signals in the form of microbial products or molecules expressed by APCs in
response to innate immune reactions to the microbes
Steps in the activation of T lymphocytes. Naive T cells recognize major histocompatibility complex (MHC)-
associated peptide antigens displayed on antigen-presenting cells (APCs) and other signals (not shown). The T cells
respond by producing cytokines, such as IL-2, and expressing receptors for these cytokines, leading to an autocrine
pathway of cell proliferation. The result is clonal expansion of the T cells. Some of the progeny differentiate into
effector cells, which serve various functions in cell-mediated immunity, and memory cells, which survive for long
periods. CTL, cytotoxic T lymphocyte; IL-2, interleukin-2; IL-2R, interleukin-2 receptor.
Role of Innate Immunity in Stimulating Adaptive Immune Responses
The TCR
• recognizes antigens,
•it is not able to transmit biochemical signals to the
interior of the cell.
•is noncovalently associated with a complex of three
proteins that make up CD3 and with a homodimer of
another signaling protein called the ζ chain
Regulation of integrin avidity
Integrins are present in a low-affinity state in resting T cells
Chemokines produced by APCs and signals induced by the TCR when it recognizes antigen both
act on integrins and lead to their clustering and to conformational changes that increase the
affinity of the integrins for their ligands
As a result, the integrins bind with high avidity to their ligands on APCs and thus promote T cell
activation. APC, antigen-presenting cell; TCR, T cell receptor.
ROLE OF COSTIMULATION IN T CELL ACTIVATION
The full activation of T cells is dependent on the recognition of costimulators on APCs
On recognition of antigens and costimulators, T cells express proteins that are involved in
proliferation, differentiation, and effector functions of the cells
Naive T cells that have not encountered antigen (so-called resting cells) have a low level of protein
synthesis
Within minutes of antigen recognition, new gene transcription and protein synthesis are seen in the
activated T cells
•T lymphocytes are the cells of cell-mediated immunity, the arm of the adaptive immune system that
combats intracellular microbes, which may be microbes that are ingested by phagocytes and live within
these cells or microbes that infect nonphagocytic cells.
•T cells use their antigen receptors to recognize peptide antigens displayed by MHC molecules on
antigen-presenting cells (which accounts for the specificity of the ensuing response) and polymorphic
residues of the MHC molecules (accounting for the MHC restriction of T cell responses)
•Antigen recognition by the TCR triggers signals that are delivered to the interior of the cells by
molecules associated with the TCR (the CD3 and ζ chains) and by the co-receptors, CD4 and CD8, which
recognize class II and class I MHC molecules, respectively
•The binding of T cells to APCs is enhanced by adhesion molecules, notably the integrins, whose affinity
for their ligands is increased by chemokines produced in response to microbes and by antigen recognition
by the TCR.
CONCLUSIONS
•The biochemical signals triggered in T cells by antigen recognition and costimulation result
in the activation of various transcription factors that stimulate the expression of genes
encoding cytokines, cytokine receptors, and other molecules involved in T cell responses
•In response to antigen recognition and costimulation, T cells secrete cytokines, of which
some induce proliferation of the antigen-stimulated T cells and others mediate the
effector functions of T cells
CD4+ helper T cells may differentiate into subsets of effector cells that produce
restricted sets of cytokines and perform different functions
•TH1 cells, which produce IFN-γ, activate phagocytes to eliminate ingested microbes,
and stimulate the production of opsonizing and complement-binding antibodies.
•TH2 cells, which produce IL-4 and IL-5, stimulate IgE production and activate
eosinophils, which function mainly in defense against helminths.
•TH17 cells, which produce IL-17, are implicated in several inflammatory diseases and
may play a role in defense against bacterial infections
CD8+ T cells recognize peptides of intracellular (cytoplasmic) protein antigens and may
require help from CD4+ T cells to differentiate into effector CTLs. The function of CTLs
is to kill cells producing cytoplasmic microbial antigens.