Immunology

APCs

APCs are antigen presenting cells, which display epitope proteins – exogenous antigen or fragmented antigen from phagocytosed cells – on their surfaces.

APC types : B cells : BCRs : CD1 family : CD1 proteins : CD4+ : class II MHC : dendritic cells : endocytosis : exocytosis : fragmented antigen peptides : histocompatibility molecules : γδ T cells : intact antigen : lipid antigen : macrophages : mycobacterial cell wall components : peptide antigen : phagocytic presenting cells : T cells and fragmented peptides, T cells and lipid antigens

Antigen presenting cells include:
phagocytic cells – dendritic cells, macrophages
B cells (B lymphocytes)
γδ T cells

Fragmented antigen – APCs engulf the antigen through endocytosis, then the endosome fuses with a lysosome where the antigen is digested into fragments such as short peptides. Following, exocytosis, a class II histocompatibility molecule holds the fragmented antigenic peptides at the surface of the cell, where they may be recognized by CD4+ T cells.

Intact antigen – dendritic cells can present intact antigen to B cells (not fragmented in lysosomes) by presenting the antigen on the cell surface. This antigen can bind to BCRs of the appropriate specificity, and can stimulate the B cells.

Presentation of peptide antigens for activation of naïve T cells does not reside solely in dendritic cells. A population of γδ T cells can efficiently present peptide antigens to αβT cells, and γδ T cells of the major tissue subset recognize self and foreign nonpeptide, lipid antigens presented by CD1 proteins. γδ T cells carry TCRs encoded by different gene segments than those of αβ T cells.

CD1 proteins are a family (CD1a-e) of cluster of differentiation glycoproteins related to the class I MHC molecules. CD1 are involved in the presentation of lipid and glycolipid antigens, particularly self, microbial, and mycobacterial cell wall components, to CD1-specific T cells.

The human CD1 family of transmembrane glycoproteins are encoded by five CD1 family genes organized in a cluster on chromosome 1. CD1 glycoproteins form heterodimers with beta-2-microglobulin. CD1 family members are considered to differ in cellular localization and specificity for particular lipid ligands. The CD1a protein (R4, T6, CD1, FCB6, HTA1) localizes to the plasma membrane and to recycling vesicles of the early endocytic system. Alternatively spliced transcript variants have been observed.[e]

ф activationalternative splicing ф antibodies ф antigen ф B cells cell membranes ф costimulation ф dendritic cellsendosomesexosome ф helper T cell ф killer T cellslysosome ф macrophages ф MHC ф pathogens ф pattern-recognition receptors ф phagocytephagocytosisreceptor-mediated endocytosis ф surface receptors ф γδ T cells ф T cells

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helper T cell

Helper T cells, T helper cells (Th), effector T cells circulate throughout the body where they interface with MHC class II protein on other cells, determining whether the MHC class II is presenting 'self' or 'non-self protein' (antigen). MHC class II receptors are located on the surface of professional antigen presenting cells (APCs), which display epitope proteins – exogenous antigen or fragmented angtigen from phagocytosed cells – on their surfaces.

When a helper T cell is activated by contact with antigen, it enters the cell cycle in addition to producing lymphokines and chemokines. Th cells direct antibody class switching in B lymphocytes, orchestrate activation and growth of cytotoxic T cells, and maximize the bactericidal activity of phagocytes (macrophages).

Naïve B lymphocytes each have one of millions of distinct surface antigen-specific surface receptors, yet have not encountered their specific, cognate antigen. With a life-span of only a few days, many B cells die without ever encountering their cognate antigen. Naïve B cells are stimulated when the BCR binds to its cognate antigen. This antigen-Ig binding must be coupled with a signal from a helper T cell in order to activate the B cell.

Helper T cells mostly carry the CD4 surface protein, though a few carry CD8. The CD4 receptor triggers targetting by HIV, which determines the crippling effect of HIV on the immune system.
Subsets of Th cells are defined by the class of cytokine that they secrete upon activation:
Th1 – produce copious amounts of IL-2 and IFN-γ.
Th2 – particularly effective at stimulating B cells through secretion of IL-4, IL-5, and IL-6.
Th3 – produce cytokine transforming growth factor-beta (TGF-β) and IL-10.


Th1 cells are the more effective antiviral agents by virtue of their secretion of interferons (IFN-γ).  Immune Cytokines  Interferons

The cytokines produced by the two Th subsets perform cross-regulatory role. An activated Th2 cell secreting IL-4,-5,and 6 downregulates local Th1 cells in the neighborhood, whereas Th1 cytokines downregulate Th2 responses.

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[] diagram - helper T cells and phagocytic response to tumor cells [] diagram - HIV binding via CD4 receptors [] micrograph germinal center with helper T cells [] tem - helper T & B cell []

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killer T cells

Cytotoxic, CTLs, or killer T cells (CD8+) release lysis-inducing lymphotoxins.

Apo_1 : apoptosis : C9 : CD8+ : CD95 : caspases : class I MHC : CIK cells : CTLs : cytotoxic T lymphocytes : epitope : Fas-FasL : granzymes : LAK cells : LAK anti-tumor Tx : membrane attack complex : MHC class I : natural killer cells : NK cells : NK receptors : perforin : perforin gene : perforin pore : serine protease : Tc : TIL cells : TNFR

TcCTL , some CTL → CIK
natural killer cells (NK)
laboratory: leukocyte + IL-2LAK
▼ anti-tumor Tx TIL, LAK

Tc cells express CD8 plus an antigen-specific T cell receptor (TCR) that ligates antigens presented by MHC class I, and are derived from a common lymphoid progenitor matured in the thymus. These Tc cells, once activated and matured into cytotoxic T lymphocytes (CTLs), recognize and destroy infected/altered self-cells.

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells lyse target cells. CTLs recognize a specific epitope peptide presented by major histocompatibility complex (MHC) class I molecules on the target cells. NK cells recognize targets that express no class I MHC molecules I or low levels of MHC I molecules, enabling NK cells to target cells that have evaded CTLs.

Evidence suggests that both NK cells and CTLs exclusively employ perforin-dependent cytolysis. Perforin is a 534 aa glycoprotein with sequence homology to the membrane attack component of complement C9. As a cytolytic mediator, perforin integrates into the target cell membrane, forming polyprotein pores up to 20nm in diameter comprising 12—18 perforin monomers, which breach membrane integrity and permitting cytolytic cell death. The cell-type-specific expression of the perforin gene is determined by the promoter and upstream region, and there is evidence of transcriptional repression of the perforin gene in non-killer cells by two novel regulatory elements, one of which that is exclusively expressed by non-killer cells appears to be an Ets family member.[p]

Perforin pores in the plasma membrane of targetted cells permit entry of serine-protease granzymes, which cleave caspase precursors and trigger apoptosis. Perforin-dependent cytolysis plays an important role in immune response to bacterial and viral infections, in tumour surveillance, in immunopathology, and in autoimmunity.

A second cytolytic mechanism is mediated by the interaction of activated T cell surface FasL with TNFR family Fas receptors (TNFRSF6, Apo_1, CD95) expressed on the surface of the target cell. Fas and TNFR1 share a a conserved extracellular region and a cytoplasmic domain, crucial for the induction of apoptosis. Targets that express Fas can be lysed upon interaction with FasL on the surface of an effector cell (usually an activated T cell) or upon cross-linking by anti-Fas antibodies. A deficiency of functional Fas—FasL interactions results in lymphoproliferation, abnormal constitution of the peripheral T cell pool, and autoimmunity. [pdf]

Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL) with the characteristic CD3+CD56+ phenotype. CIK cells also express CD94, part of the NK receptor comprising of CD94-NKG2 heterodimer. CIKs have demonstrated higher proliferative and cytolytic activities in comparison to the reported CD3-CD56+ lymphokine activated killer (LAK) cells that are essentially activated natural killer (NK) cells. CIK cells are non-MHC-restricted in target cell recognition and killing.

Lymphokine-activated killer cells (LAKs) are leukocytes stimulated in the laboratory to kill tumor cells. LAKs are generated by culturing spleen or peripheral blood leukocytes in presence of high concentrations of IL-2. LAKs are T-like cells that express CD3 or CD8. They lyse targets non-specifically, and with a target range hierarchy different than that of NK cells. LAK cells respond chemotactically and accumulate at sites of viral infection.

Natural killer (NK) cells are very important components of the innate immune system, are distinct from CTLs. NK, natural killer cells constitute a corps of circulating lymphocytes that are constitutively specialized to attack cancerous cells and virus infected cells. Preprogramming for target recognition, coupled with the absense of need for backup by a clone of identical cells, renders NK cells capable of rapid (innate) response to pathogens.

Individuals inherit multiple, polymorphic genes for NK receptors, so the assemblage of NK receptors differs between individuals. NK cells carry two forms of surface receptors:
killer inhibitory receptors (KIR) belonging to the immunoglobulin superfamily. KIRs transmit an inhibitory signal when they encounter class I MHC molecules on a cell surface. (By contrast, T cells only recognize antigens that are presented by a MHC molecule.)
activating receptors, which activate the NK cell upon binding to a target cell
-- ● killer lectin like receptor (KLR) CD94/NKG2 heterodimer, which employs MHC as ligand
-- ● natural cytotoxic receptors (NCR) which do not associate with MHC.

Lymphokine-activated killer (LAK) and tumor-infiltrating lymphocytes (TIL) have been employed therapeutically since the '70s mainly in end-stage patients with solid tumors. TIL are more specific and potent cytotoxic effectors than LAK, but their clinical use be considered potentially useful only in a few patients, chiefly those with solid tumors such as melanoma and glioblastoma.[r]

TcCTL , some CTL → CIK
natural killer cells (NK)
laboratory: leukocyte + IL-2LAK
▲ anti-tumor TIL, LAK

▲ ф antibodies ф antigen : Apo_1 : apoptosisapoptosis ф B cells : C9 ф C9: CD8+ : CD95 ф CD : caspases : class I MHC ф complement system ф classes of MHC : CTLs ф cytolysis : cytotoxic T lymphocytes : epitope : Fas-FasL ф granulocytes : granzymes : membrane attack complex ф membrane attack complex ф MHC : MHC class I : natural killer cells ф : NK cells ф NK cells : perforin : perforin gene : perforin pore ф C9 pore ф receptors : serine protease ф serine proteases ф surface receptors : Tc : TNFR

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