Page 19 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 1 The Human Immune Response 5

express receptors for PAMPs and, as such, serve as major effectors cells, monocytes (present in the peripheral circulation), macro-
of innate immunity. They also recognize target cells that might phages (solid tissue derivatives of monocytes), cutaneous
otherwise elude the immune system (Chapters 2, 17). Thus Langerhans cells (Chapter 19), and constituents of the reticular
recognition of NK cell targets is based substantially on what endothelial system within solid organs. B lymphocytes that
their targets lack rather than on what they express. NK cells specifically capture antigen via their clonally expressed mIg can
express receptors of several types for major histocompatibility also function efficiently in antigen presentation to T cells.
complex (MHC) class I molecules via killer immunoglobulin-like Cardinal features of APCs include their expression of both
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receptors (KIRs). KIRs are expressed on the plasma membrane class I and class II Major Histocompatibility Complex (MHC;
of NK cells (and some T cells), which interact with class I Chapter 5) molecules as well as requisite accessory molecules
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molecules to alter NK-cell cytotoxic function. Most KIRs express for T-cell activation (e.g., B7-1, B7-2/CD80, CD86). Upon
in their intracellular domain a tyrosine-based inhibitory-motif activation, APC elaborate cytokines that induce specific responses
(ITIM) that suppresses NK activity, thereby preventing NK cell in cells to which they are presenting antigen. In addition to
activity directed against normal self-cells. In contrast, some KIRs processing and presenting antigen, APCs can regulate activation
express a tyrosine-based activation motif (ITAM), which amplifies of the immune system via innate cell surface receptors, which
their activity. NK cells will kill target cells unless they receive an contribute to determination of whether the antigen is pathogen
inhibitory signal transmitted by an ITIM receptor. Virus-infected associated.
cells and tumor cells that attempt to escape T-cell recognition APCs differ substantially among themselves with respect to
by downregulating their expression of class I molecules become mechanisms of antigen uptake and effector functions. Immature
susceptible to NK cell–mediated killing because the NK cells dendritic cells show high phagocytic and pathogen-killing activity
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receive an activation signal and/or fail to receive an inhibitory but low ability to present antigen and activate T cells. Dendritic
signal through the ITAM- and ITIM-containing MHC class I cells (DCs) that have ingested a pathogen or foreign antigen can
receptors. The balance between ITIM and ITAM is regulated by be induced to mature by inflammatory stimuli, especially via
the microenvironmental milieu, increasing expression of ITAM cells of the innate immune system and by direct activation through
in the presence of viral-infected or cancer cells and of ITIM as receptors for PAMPs or DAMPs. 12,13 Monocytes and macrophages
necessary to maintain self-tolerance and prevent autoimmunity. are actively phagocytic, particularly for antibody and/or
A high frequency of ITAM-expressing cells has been reported complement-coated (opsonized) antigens that bind to their
in some patients with autoimmune diseases. 9 surface receptors for IgG and C3b. These cells are also important
Although NK cell–mediated innate immunity has been long effectors of immune responses, especially in sites of chronic
considered to lack immunological memory, recent studies suggest inflammation. Upon further activation by T-cell cytokines, they
that NK cells can exhibit memory of previous encounters with can kill ingested microorganisms by oxidative pathways similar
microbes or other antigens, the molecular basis of which remains to those employed by polymorphonuclear leukocytes.
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to be fully elucidated. NK cells can also participate in antigen- The interaction between B cells acting as APCs and T lym-
specific immune responses by virtue of their surface display of phocytes is notable as the cells are involved in a mutually
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the activating ITAM receptor CD16, which binds the constant amplifying circuitry of antigen presentation and response. The
(Fc) region of IgG molecules. This enables them to function as process is initiated by antigen capture through B cell mIg and
effectors of a cytolytic process termed antibody-dependent cellular ingestion by receptor-mediated endocytosis. This is followed by
cytotoxicity (ADCC), a mechanism exploited clinically with proteolytic antigen degradation and then display to T cells as
monoclonal antibody (mAb) therapeutic agents. 11 oligopeptides bound to MHC molecules. Like other APCs, B
In general, pathways leading to differentiation of T cells, B cells display CD80, which provides a requisite second signal to
cells, and ILCs are mutually exclusive, representing a permanent the antigen-responsive T cell via CD28, its accessory molecule
lineage commitment. No lymphocytes express both mIg and for activation (Fig. 1.1). As a result of T-cell activation, T-cell
TCRs. However, a subset of T cells, termed NKT cells, exhibit cytokines that regulate B-cell differentiation and antibody produc-
both NK-like cytotoxicity and αβTCR with limited receptor tion are produced, and T cells are stimulated to display the surface
diversity. ligand CD40L (CD154), which can serve as the second signal
for B-cell activation through its inducible surface receptor
Antigen-Presenting Cells
BASIS OF ADAPTIVE IMMUNITY
KeY ConCePtS
Features of Antigen-Presenting Cells The essence of adaptive immunity is molecular distinction
between self constituents and potential pathogens (for simplicity,
• Capacity for uptake and partial degradation of protein antigens self/nonself discrimination, but perhaps more precisely discrimi-
• Expression of major histocompatibility complex (MHC) molecules for nation between molecular species perceived as signaling potential
binding antigenic peptides “danger” and those that do not). This discrimination is a major
• Chemokine receptors to allow colocalization with T cells responsibility of both T lymphocytes and cells of the innate
• Expression of accessory molecules for interaction with T cells immune system. It reflects the selection of thymocytes that have
• Receptors for pathogen- or danger-associated molecular patterns
• Secretion of cytokines that program T helper (Th) cell responses generated specific antigen receptors, which, upon later encounter,
can bind nonself antigenic peptides bound to self-MHC molecules.
The consequence of this selection process is that foreign proteins
A morphologically and functionally diverse group of cells, all are recognized as antigens, whereas self-proteins are tolerated
of which are derived from bone marrow precursors, is specialized (i.e., are not perceived as antigens). Additionally, the cells of
for presentation of antigen to lymphocytes, particularly innate immunity contribute importantly, through PAMPs/DAMPs
T cells (Chapter 6). Included among such cells are dendritic and several mechanisms still being defined, to the essential