Immunology

CD

CD stands for cluster of differentiation, which indicates a defined subset of cellular surface receptors (epitopes) that identify cell type and stage of differentiation, and which are recognized by antibodies.

There are more than 250 identified clusters, each a different molecule, coating the surface of B lymphocytes and T lymphocytes.

All T and B cells have about 105 = 100,000 molecules on their surface. B cells are coated with CD21, CD35, CD40, and CD45 together with non-CD molecules, while T cells express CD2, CD3, CD4, CD8, CD28, CD45R, and other non-CD molecules. Many CDs are expressed on both B and T cells, including CD5, CD6, CD23, CD27, CD28, CD84. Dendritic cells also express CD4 and CD8.

▼ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD1 : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD25 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR▼

T cell CDs:

CD2 family receptors are immunoglobulin (Ig) superfamily type I transmembrane, glycosylated proteins characterized by an N-terminal variable (V) domain that lacks disulfide bonds and a truncated Ig constant 2 (C2) domain that has two disulfide bonds in the extracellular region.

CD3 family receptors comprise three distinct chains – CD3γ, CD3δ and CD3ε in mammals – which are closely related proteins of the immunoglobulin superfamily, each containing a single extracellular immunoglobulin domain. The CD3 chains associate with TCRs and the ζ-chain to activate T lymphocytes. Together the TCR, ζ-chain, and CD3 molecules consitute the TCR complex.

The transmembrane region of the CD3 chains is negatively charged, enabling these chains to associate with the positively charged TCR chains (TCRα and TCRβ). The intracellular tails of the CD3 molecules contain a single conserved motif termed the immunoreceptor tyrosine-based activation motif (ITAM) that is essential for TCR signaling. Phosphorylation of CD3's ITAM enables the CD3 chain to bind Fyn, a membrane-associated protein tyrosine kinase important in the T cell's signaling cascade.

CD4 is notorious because of its importance in HIV/AIDs. It is an approximately 55 kDa type I membrane glycoprotein expressed predominantly on T cell precursors and a subset of mature T cells, providing the surface protein to which HIV attaches itself in order to invade the cell. CD4 is also found on the surface of monocytes, macrophages, Langerhans cells, astrocytes, keratinocytes and glial cells. The number of serum T4 cells is employed to measure the health of the immune system in people infected with HIV.[R&D]

CD8 (T8) is a protein embedded in the cell surface of 'suppressor' or regulatory T lymphocytes (Treg).

The CD31 adhesion molecule (PECAM-1) is expressed in large amounts at intercellular junctions of endothelial cells, subsets of T cells, platelets, and most other leukocytes including monocytes and neutrophils. CD31 is required for the trans-endothelial migration – extravasation – of leukocytes through intercellular junctions of vascular endothelial cells.

CD58 is also known as lymphocyte function-associated antigen (LFA-3). CD58 is a cell-bound immunoglobulin superfamily receptor with only one known ligand, which is CD2. CD58 is widely expressed on human hematopoietic and non-hematopoietic tissues, leukocytes, erythrocytes, endothelial and epithelial cells, and fibroblasts. The receptor-ligand pair, CD58 plus CD2, optimizes immune recognition and initiates T cell expansion and activation. Such contact activities can occur between helper T cells and antigen-presenting cells and between cytolytic effectors and target cells.

B and T cell CDs:

C5 is a 67 kDa surface glycoprotein of the scavenger receptor cysteine-rich (SRCR) superfamily that appears on thymocytes, mature T cells, and B cells. CD5 is important for the apoptosis of antigen-receptor induced B lymphocytes and for the maintenance of tolerance by anergic B cells. CD5 crosslinking induces extracellular mobilization of calcium ions, tyrosine phosphorylation of intracellular proteins, and production of diacylglycerol. Infection by EBV downregulates CD5 expression, while the glycoprotein is expressed in many T-cell leukemias and lymphomas.

CD6 is a member of the group B scavenger receptor cysteine-rich (SRCR) superfamily, which is expressed at low levels on immature thymocytes, at high levels on mature thymocytes, on the majority of peripheral blood T cells, a subset of B cells, and a subset of neuronal cells. Human and mouse CD6 proteins share 70% amino acid sequence identity over their full lengths.

CD23 is the receptor for the Fc portion of IgE.

CD27 Ligand/TNFSF7 is also known as CD70, and is a type II transmembrane glycoprotein belonging to the TNF superfamily (TNFSF). The expression of CD27 Ligand is induced by antigen-receptor activation in B cells. CD27/TNFRSF7 is a lymphocyte-specific member of the TNF receptor superfamily, which is expressed on a subset of human T cell precursors (thymocytes), on the majority of mature T cells, on natural killer (NK) cells, and subsets of B cells. CD27 ligation on NK cells induces proliferation and production of IFN-γ. CD27 binding (ligation) to T cells provides a co-stimulatory signal required for T cell proliferation, the promotion of effector T cell formation, and clonal expansion. The binding of CD27 to B cells inhibits the terminal differentiation of activated B cells into plasma cells and instead enhances commitment to memory B cell responses.

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2, constitute one of the dominant B and T cell costimulatory pathways. CD28 and CTLA-4 are structurally homologous molecules of the immunoglobulin (Ig) gene superfamily. Mouse CD28 is expressed constitutively on almost all mouse T cells and on developing thymocytes.

CD45 is a protein tyrosine phosphatase (PTP) that regulates Src kinases required for T and B cell receptor signal transduction. CD45 dephosphorylates a negative regulatory residues on one or more of the protein tyrosine kinases that are involved in receptor-mediated second messenger formation. CD45 is located in all hematopoietic cells except erythrocytes and platelets, so it is also called the common leukocyte antigen.[]rotatable im[]

The CD45-regulated Src kinases are Lyn and Blk in B cells, and Lck and Fyn in T cells. ITAMs are immunocreceptor tyrosine bases motifs comprising two tyrosine residues separated by amino acids. RTK-phosphorylation of ITAMS enables them to bind to second family protein tyrosine kinases such as CD45, for which their SH2 domains have high binding affinity. In T cells, CD45 phosphorylates Csk, which is an inhibitory protein tyrosine kinase that controls tyrosine activity in lymphocytes. In B cells, calcium ions are transduced by the BCR, inducing CD45 expression. CD45RO, CD45RA, and CD45RB are isoforms of CD45.


CD84 is also known as Ly-9B, and is a member of the CD150/SLAM (signaling lymphocyte activation molecule) subfamily of the CD2 family (designated SLAMF5). CD84 is expressed on B cells, T cells, monocytes and platelets and acts as a self-ligand. Human and mouse CD84 share approximately 57% amino acid sequence identity.

B cell CDs:

CD40 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 is expressed on B cells, follicular dendritic cells, dendritic cells, activated monocytes, macrophages, endothelial cells, vascular smooth muscle cells and several tumor cell lines. Human and mouse CD40s have 64% identity of amino acid sequence identity.


CD72 is a 39-43 kDa type II membrane glycoprotein of the C-type lectin family. CD72 is a pan-B cell marker that is expressed throughout the B lymphocytes differentiation (except plasma cells). CD72 is also present on follicular dendritic cells.

Monocytes/Macrophages

CD14 is a 55 kDa cell surface glycoprotein that is preferentially expressed on monocytes and macrophages. The amino acid sequence of human CD14 is approximately 65% identical to mouse CD14, and 82% identical to rat proteins.

Also: CD4, CD31 adhesion molecule (PECAM-1), CD40, CD84

Platelets:

CD36 is also known as scavenger receptor class B member 3 (SR-B3), GPIIIb, platelet membrane glycoprotein IV (GPIV), collagen receptor, thrombospondin receptor, and fatty acid translocase (FAT). CD36 is a broadly-expressed integral membrane glycoprotein with multiple physiological functions. As a member of the scavenger receptor family, CD36 is a multi-ligand pattern-recognition receptor that interacts with a large number of structurally dissimilar ligands. Upon ligand binding, CD36 transduces signals that mediate a wide range of pro-inflammatory cellular responses.

Complement CÆ activation family (RCA):

CD55, also known as decay-accelerating factor (DAF), is a 70 to 75 kDa member of the regulators of complement/CÆ activation (RCA) family of proteins. It is ubiquitously expressed on cells that are exposed to plasma complement proteins. Human CD55 is synthesized as a 381 amino acid precursor that comprises a 34 aa signal sequence, a 319 aa mature region and a 28 aa C-terminal prosegment.

Costimulatory:

CD28 and CTLA-4, together with their ligands, B7-1 and B7-2.

Pattern-recognition receptors :

CD36

Glycoproteins:

CD4, CD5, CD14, CD27, CD30, CD36, CD40, CD72

Immunoglobulin superfamily:

CD2, CD58, CD28 and CTLA-4,
CD23 is the receptor for the Fc portion of IgE.

LFA (lymphocyte function associated antigen):

CD58

migration:

CD31 adhesion molecule (PECAM-1)

Scavenger receptor (SRCR) family:

CD5, CD6, CD36

SLAM (signaling lymphocyte activation molecule) subfamily:

CD84 (Ly-9B), CD2 family (SLAMF5)


TNFRs :

CD30/TNFRSF8 is a type I transmembrane glycoprotein belonging to the TNF receptor superfamily, where the the ligand for CD30 is CD30L (CD153, TNFSF8), which is a member of the TNF superfamily. CD30 binding by CD30L mediates pleiotropic effects, including cellular proliferation, activation, differentiation, and apoptosis.

Other TNFRs are CD40 and CD27.

Miscellaneous CDs
CD9 is a member of the tetraspanin transmembrane receptor family. CD9 contains four putative transmembrane domains and two extracellular loops, and is thought to be involved in egg-sperm fusion. Several reports indicate that CD9 associates with integrins and affects cell behavior on fibronectin surfaces (ref).[s]

▲ B lymphocyte CDs : B and T lymphocyte CDs : T lymphocyte CDs : TNFRs : CD2 : CD3 : CD4 : CD5 : CD6 : CD8 : CD14 : CD23 : CD27 : CD28 : CD30 : CD31 : CD36 : CD40 : CD45 : CD45 isoforms : CD55 : CD58 : CD72 : CD84 : complement CÆ : costimulatory : ITAMs : LFA : lymphocyte function associated antigen : glycoproteins : Ig superfamily : Macrophages/Monocytes : migration : pattern recognition receptors : platelets : scavenger receptors : SLAM (signaling lymphocyte activation molecule) : TNFR ▲

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[C][CD5][CD72] Tables  Fc receptors  Immune Cytokines  Immunoglobulins


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hematopoiesis

Hematopoiesis is the production of blood cells, a developmental process located in the (red) bone marrow, though some cells mature elsewhere. For example, T lymphocytes are so named because they mature in the thymus, and antigenic stimulation of B lymphocytes to become plasma cells typically takes place in the periphery.

▼ B lymphocyte development : common lymphoid progenitor : common myeloid progenitor : E2A : EBF : early B lineage : erythropoiesis : granulopoiesis : hematopoietic growth factors : lymphopoiesis : monocytopoiesis : Pax-5 : pluripotential stem cell : precursors : progenitors : regulatory transcription factors : stages : stem cells : thrombopoiesis : transcriptional regulatory proteins▼

The process of haematopoiesis occurs in several stages, and is controlled by at least 11 hematopoietic growth factors (including the colony-stimulating factors, IL-2 through IL-7, G-CSF, GM-CSF, and M-CSF). The first stage involves the differentiation of a pluripotential stem cell into a committed progenitor, which is followed by maturation of committed progenitors in distinct pathways, in which precursors are partially developed, 'adolescent' cells en route to maturity.

stem → progenitor → precursor → adult → mature

[] labeled photomicrograph of bone marrow, diagram of adult stem cell plasticity, diagram of stem cell versus progenitor cell

Stem cell stage:
pluripotential hematopoietic stem cell
↓ --------------------↓

The common myeloid progenitor can generate:

● proerythroblasts (pronormoblasts) → erythropoiesis

● myeloblasts → granulopoiesis

● monoblasts → monocytopoiesis

● megakaryoblasts → thrombopoiesis

The common lympoid progenitor can generate:

● lymphoblasts → lymphopoiesis

۝

Committed progenitor stage to mature cell : granulopoiesis

common myeloid progenitor

↓

myeloblast

↓

B/E/N promyelocyte

↓---↓---↓

B/E/N myelocyte

↓---↓---↓

B/E/N metamyelocyte

↓---↓---↓

B/E/N band

↓---↓---↓

basophil, eosinophil, neutrophil

↓ -----------------------

mast cell -----------------------

۝

Committed progenitor stage to mature cell : lymphopoiesis

common lymphoid progenitor

↓

lymphoblast

----------------------------------------↓ rearrangements H: D-J → H: V-DJ

prolymphocyte

-----------------↓ rearrangements L: V-J --------------------------↓

small lymphocyte------or----- natural killer cell (large granular lymphocyte)

------------↓ IgM→IgD ---------↓------------------------------------ ↓

------B lymphocyte--or-- T lymphocyte

------------↓----------------------------------------------------------- ↓

--------plasma cell------------------------------------------lymphoid dendritic cell

Development of mature B lymphocytes from multipotent progenitors requires the coordinated activities of a number of transcriptional regulatory proteins, including EBF, Pax-5, and E2A.

During B cell-development from the precursor stage, differentiation involves rearrangement of the heavy chain gene segments. The functional integrity of the rearranged gene is tested: Precursor-B cells express two single domain Ig-like proteins of invariant sequence that substitute for the light chain. Formation of a complex comprising the μ (mu) heavy chain with the surrogate light chains instructs the cell to discontinue rearrangement of the heavy chain locus and to commence rearrangement of the k (kappa) locus. If successful light chain rearrangement is achieved such that the light and heavy chains form a complete antibody, then this complex instructs the cell to discontinue rearrangement of light chains, ensuring that only a single specificity is produced (allelic exclusion). Џ B cell maturation - animation Џ

Those developing B cell clones that fail to generate a productive rearrangement at both one of their heavy chain alleles and a light chain locus will undergo apoptosis. Immune tolerance mechanisms also exist to ensure the death of any newly produced B cells that express an antibody that reacts strongly with self proteins on the surface of host cells.

E2A proteins function in early B lineage development to regulate B lineage-specific gene expression as well as B cell survival. E2A-encoded proteins are involved in the differentiation of a number of cell types, and they are especially important in lymphocyte development.

The E2A gene encodes E47 and E12, which are basic-helix-loop-helix (bHLH) transcription factors that bind DNA either as homodimers or as heterodimers with other bHLH proteins. Such bHLH DNA binding activity in the B-lineage comprises E47 homodimers. Development of thymocytes mainly involves heterodimers of E47 and a related bHLH protein, HEB. Thymocytic E2A protein expression is required to initiate T-cell differentiation. During the development of thymoctyes, E-proteins and their antagonists, Id2 and Id3, regulate T-lineage specific gene expression and TCR rearrangement. E2A and Id proteins block thymocytic maturation in the absence of pre-TCR expression, and pre-TCR signaling acts to promote development in part by inhibiting E2A activity. [l]

۝

Committed progenitor stage to mature cell : monocytopoiesis

common myeloid progenitor

↓

monoblast

↓

promonocyte

↓

monocyte

↓ ----↓

macrophage or myeloid dendritic cell


۝

Committed progenitor stage to mature cell : erythropoiesis

common myeloid progenitor

↓

proerythroblast

↓

basophilic erythroblast

↓

polychromatic erythroblast

↓

polychromatic erythrocyte (reticulocyte)

↓

erythrocyte (RBC)

۝

Committed progenitor stage to mature cell : thrombopoiesis

↓
megakaryoblast
↓
promegakaryocyte
↓
megakaryocyte
↓
thrombocytes (platelets)

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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 ▼

▼ Tc → CTL , some CTL → CIK
▼ natural killer cells (NK)
▼ laboratory: leukocyte + IL-2 → LAK
▼ 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]

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

▲ ф antibodies ф antigen : Apo_1 : apoptosis סּ apoptosis 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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Tables  Complement Receptors  Fc receptors  Immune Cytokines  Immunoglobulins  Interferons  Scavenger Receptors  Toll-like Receptors  Cell Adhesion Molecules  Cell signaling  Receptor Tyrosine Kinases (RTKs)  Receptor Signal Transduction  Second Messengers

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lymphokines

Lymphokines comprise that subset of cytokines produced by T lymphocytes, whereas monokines are secreted by monocytes. Modern usage employs the more general term 'cytokine'.

Lymphokines include:
● colony-stimulating factors (CSFs), including GM-CSF
● interferons (IFNs) - IFNγ
● interleukins IL-1 to IL-8, IL-10, IL-13
● macrophage inflammatory protein-1 beta (MIP-1β)
● neuroleukin (lymphokine product of lectin-stimulated T cells)[s]
● osteoclast-activating factor
● platelet-derived growth factor (PDGF)
● transforming growth factor beta (TGFβ)
● tumour necrosis factor-alpha (cachectin) (TNFα)
● tumour necrosis factor-beta (TNFβ, lymphotoxin α, LT)

Actions of lymphokines include
● activates B cells, inhibits macrophage function – IL-10
● activation of neutrophils, eosinophils, and monocyte/macrophages – GM-CSF
● bone resorption – osteoclast activating factor
● bone marrow – growth and differentiation of immune cells – IL-3
● B cell growth and differentiation – IL-4
● B cell differentiation, activates some microphages (PMN) – IL-5
● costimulator of T cells, induces growth in B cells – IL-6
● inflammation, fever, catabolism and cachexia, activation of some microphages – TNFs
● hematopoiesis stimulators – IL-3, IL-7, GM-CSF
● macrophage-activating activity (MAF) – IFN-γ
● stimulates proliferation of activated T and B cells – IL-2
● inhibits T cell growth, activates macrophages – TGFβ

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lymphoid system

Components of the lymphoid system are:
● immune cells – B cell lymphocytes and plasma cells, dendritic cells, granulocytes, macrophages, monocytes of mononuclear phagocyte system (MPS), T cell lymphocytes
● lymph ducts and vessels and lymph nodes (right)
[] histopathology []
● lymphoid organs including reticuloendothelial system – bone marrow, (lymph nodes), mucosa-associated lymphoid tissue, Peyer's patches, spleen, thymus, tonsils, vermiform appendix

The reticuloendothelial system or mononuclear phagocytic system comprises a range of cells that are capable of phagocytosis, including macrophages and monocytes. Phagocytosis is an innate immune process, and is not an adaptive immune process. The phagocytic cells either circulate in the blood or are attached to various connective tissues such as pulmonary alveoli, liver sinusoids, skin, spleen, and joints.

The RES functions to provide phagocytic cells for both the inflammatory response and immune responses (primary RES) and to remove pathogens and senescent cells from circulation (secondary RES)

The reticuloendothelial system (RES) includes:
● primary (central) lymphoid production organs – bone marrow, thymus
● secondary (peripheral) lymphoid function organs – circulating monocytes, histiocytes located in many tissues, Kupffer cells of the liver, "Littoral cells" of the spleen, mucosa-associated lymphoid tissue (MALT), which is subdivided into bronchus-associated lymphoid tissue (BALT) and gut-associated lymphoid tissue (GALT), Peyer's patches.

Tables  Fc receptors  Immune Cytokines  Immunoglobulins

o-o index of tissue micrographs [] germinal centers [] fluorescence microscopy dendritic cell uptake of dying cells within spleen [] micrograph red pulp of spleen [] micrograph splenic red pulp [] micrograph spleen cells (mouse) DAPK2 stained [] micrograph white pulp, splenic nodule [] micrograph white pulp infiltrate with Langhans giant cell [] histopathology spleen Gaucher's disease [] micrograph gallery cell surface antigens [] Virtual Histology Main []


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T cells

T cells or T lymphocytes are specialized lymphocytes distinguished by their TCR surface receptors.

▼ activation T reg : APC : apoptosis : B7-1 : B7-2 : CD8 + : CD28 : CD80 : CD86 : costimulation : CTL : cytotoxic T lymphocytes : Fas-FasL : γδ T cells : granulysin : granzyme : helper T cell : IL-2 : interleukin-2 : natural killer T cells : NKT : perforin : pore : self-protection : serine protease : Tc : Th : Treg : Treg activation/action : T cell types : VDJ recombination ▼

'T' lymphocytes initially develop in the thymus, and differentiate peripherally into several functional subsets of cells:
● cytotoxic T cells – CTL, Tc – CD8 +
● helper T cells, effector T cells – Th – CD4 +
● regulatory T cells –Treg (formerly termed 'suppressor' T cells)
● natural killer T cells – NKT (different than NK cells)
● γδ T cells

Cytotoxic T lymphocytes (CTLs) or killer T cells express antigen-specific, VDJ recombination-generated TCRs plus glycoprotein CD8 on their surfaces. The TCR recognizes specific antigenic proteins that are fragmented into peptides and then are presented in complex with MHC class I molecules (MHC-peptide complex - red).

APCs provide synergistic signaling by costimulatory molecules. APC signaling is necessary to sustain and integrate TCR signaling and to stimulate optimal T cell proliferation and differentiation.

The binding of TCR•antigen•CD8•MHC-I holds the activated CTL (Tc) in proximity to the damaged/infected target cell. Once activated, the Tc cell undergoes clonal expansion with the assistance of a cytokine, interleukin-2 (IL-2) that acts as a growth and differentiation factor for T cells. (Table  Immune Cytokines)

CD28 binds the CD80 (B7-1) and CD86 (B7-2) ligands that are expressed on antigen presenting cells (APCs). When exposed to infected/dysfunctional somatic cells, Tc cells release perforin, which form pores in the target cell's plasma membrane. Also released from Tcs are granulysin and the serine protease granzyme, which transit the perforin pore and induce apoptosis of the target cell.

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.

Helper T cells (Th), or 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). Th cells direct antibody class switching in B lymphocytes.

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

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.

Regulatory cells (Treg)
Regulatory T cells were formerly called suppressor T cells because they suppress immune responses. Negative regulatory functions have been ascribed to several T cell types:
● CD4+CD25+
● CD4+CD25–
● interleukin-10-producing TR1 cells
● transforming growth factor-ß-secreting TH3 'regulatory' cells
[v]

Treg cells express the αβ TCR chains and are activated only when the TCR binds to its cognate peptide-class II MHC molecule and receives costimulation from B7 molecules (CD80, CD86) on the antigen-presenting cell. Once activated, Treg secrete interleukin 9 (IL-9), interleukin 10 (IL-10), +/- transforming growth factor-beta (TGF-β), and these lymphokines inhibit Th1 assistance of cell-mediated immunity and inflammation, and
Th2 assistance of antibody production, and may inhibit the action of CD8+ CTLs.

Because the antigenic peptides recognized by Treg TCRs are typically self-peptides, the chief function of Treg cells is provision of self-protection by preventing other T cells from attacking self components, thus protecting against autoimmunity.

CD25, or IL-2 receptor alpha chain, or IL-2R, or Tac antigen is a 55kDa glycoprotein whose transcription is regulated by Stat5, Elf-1, HGG-I(Y), GATA, and Tax from HTLV-1. CD25 is expressed on PHA-stimulated T cells, B cells stimulated with anti-IgM antibody, monocytes/macrophages stimulated with LPS, and highly expressed on HTLV-I-transformed T cell lines. NCBI LocusLink Record: 3559

Natural killer T cells – NKT cells are activated by group 2, CD1d molecules to secrete interferon-γ (IFNγ) and IL-4, which act as Th1 and Th2 cytokines.

γδ T cells carry TCRs encoded by different gene segments than those of αβ T cells. CD27 is cell-surface marker for T-cell progenitors that are beginning to undergo commitment to the αβ or γδ T-cell lineages, and newly emerging αβ and γδ T-lineage cells display early differences in dependence on Notch–Delta signaling and display distinct patterns of gene expression.[npg]

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, which comprise the predominant mammalian T cell population. Thus, γδ T cells function to bridge the innate and adaptive immune responses.

γδ T cells can form unique memory subsets with distinct adhesion and chemotactic capabilities, determining the tissue homing capabilities of cells. γδ T cells are enriched in areas of inflammation. Human γδ T cells express ligands for E- and P-selectins, so they display specialized homing to epithelial surfaces. The memory γδ T cells express chemokine family receptors not expressed by αβ T cells.

Human γδ T cells that express Vγ2Vδ2 TCRs can recognize nonpeptide antigens and Non-Hodgkin's B cell lymphomas. In particular, recognition of prenyl pyrophosphates is performed by this extracellular presentation pathway, which is distinct from MHC and CD1 presentation, and which is important in many different bacterial and parasitic infections. However, γδ T cells of the major tissue subset recognize self and foreign nonpeptide antigens presented by CD1. These nonpeptide antigens are lipids and glycolipids presented by CD1 proteins, which are MHC-like-molecules specialized for the presentation of lipids.[s].


▲ф ф antibodies ф antigen : APC ф APCs : apoptosis סּ apoptosis : B7-1 : B7-2 ф CD : CD8 + : CD28 : CD80 : CD86 סּ cell growth סּ cell membranes ₪ cellular fate : costimulation ф costimulation : CTL ~ cytokines ф cytolysis : cytotoxic T lymphocytes ₪ differentiation : Fas-FasL : γδ T cells : granulysin § granulysin : granzyme : helper T cell ф helper T cell : IL-2 ~ immunoglobulins : interleukin-2 ф immune cytokines  Immune Cytokines : killer T cells ф killer T cells ф lymphocytes ф lymphokines ф MHC : natural killer T cells : NKT : perforin : pore ф receptors : serine protease ф signaling ф surface receptors: Tc : Th : Treg : T cell types ф thymus : VDJ recombination ф VDJ recombination ▲ф

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