B and T cell functions

ADAPTIVE IMMUNITY Humoral immunity/ Antibody-mediated immunity (B cells) 1: processing of a pathogen by an antigen presenting cell and presentation of it on class II MHC molecules to an antigen-specific helper T cell activates the helper T cell to produce cytokines IL-2, IL-4 and IL-5. These cytokines activate a B cell having that same antigen-specific receptor to produce antibodies against that particular antigen. 2. An alternative pathway of B cell activation is the T-independent way, involving no helper T cells and thus no IL-4 and IL-5. It requires receptor aggregation or a strong cross linking of BCR with other PRRs. Cell-mediated immunity (T cells) 1: A bacrteria taken up by a macrophage, degraded and is presented on class II major histocompatibility complex proteins (MHC II) that interacts with the specific antigen-specific receptor on a helper T cell, this activates the T cell to proliferate and produce cytokines (IL-2, IFN-γ). 2: A virus infects cells of the respiratory tract, a viral particle is presented on class I MHC proteins and recognized by an antigen-specific receptor on a cytotoxic T cell it then proliferates with the help of IL-2 from helper T cells, and specifically kill the virus infected cells.

Humoral Immunity Cell-Mediated Immunity Microbe Extracellular bacteria Processed by an APC Extracellular microbes phagocytosed in a macrophage Intracellular microbes replicating in infected cells Responding lymphocyte B lymphocytes T lymphocytes Cell Interactions Cytokine secretion T-dependent: APC MHC II-TCR and IL-10 production. Naïve CD4+ T cell  Th2 cells secreting IL-2, IL-4 and IL-5  B cell Plasma cell *T-independent: BCR aggregation or cross linking APC MHC II-TCR and IL-12 production. Naïve CD4+ T cell  Th1 cells secreting IL-2 and IFNγ  macrophage activation APC or virus infected cell presents Ag on MHC I to TCR. Naïve CD8+ T cell  CTL (cytotoxic T lymphocyte) Effector mechanism Secreted antibodies-elimination of bacteria Activation of macrophages- microbial killing Lytic granules (containing granzymes and perforin) and FasL expression- Lysis of infected cells

T cell migration and activation

T cell activation can be induced by antigens in the presence of accessory cells- the APCs (not by a soluble antigen) or viral antigens on an infected cell

Naïve T cells first encounter antigens presented by DCs in the SLO Left: Naive T cells (blue and green) recirculate through secondary lymphoid organs, such as the lymph node shown here. They leave the blood at high endothelial venules and enter the lymph-node cortex, where they mingle with professional antigen-presenting cells (mainly dendritic cells and macrophages). T cells that do not encounter their specific antigen (green) leave the lymph node in the efferent lymph and eventually rejoin the bloodstream. T cells that encounter antigen (blue) on antigen-presenting cells are activated to proliferate and to differentiate into effector cells. These effector T cells can also leave the lymph node in the efferent lymph and enter the circulation. Right: The circulation of T cells involves their entry into lymph nodes (a) from blood via high endothelial venules (HEV), in a process dependent on CCR7 and adhesion molecules. Most cells at this stage are naive T cells (N) that, once they are in the parenchyma, encounter dendritic cells that present them with antigens ferried from the periphery through afferent lymphatics. Recognition of the appropriate antigen by incoming T cells will lead to their differentiation into effector cells (E), which now express other chemokine receptors (small circles) on their surfaces. Exit through efferent lymphatics will bring the T cells into the systemic circulation and into areas where inflammatory chemokines may be produced (b). Once in the tissue, effector T cells will produce cytokines and chemokines or undertake cytotoxic functions. At this point, they may undergo reprogramming of gene expression and convert into effector-memory T cells (E-M). Among the genes reprogrammed may be Ccr7. T cells expressing CCR7 will probably interact with lymphatic endothelial cells expressing CCL21. CCR7 will again serve as a 'passport' for entry of T cells into the lymph node, this time via afferent lymphatics. A. Naïve T cells entry from blood to lymph nodes via high endothelial vanules (HEV) is dependent on adhesion molecules and CCR7. Encounter with an Ag presenting DC coming from the afferent lymphatics will increase the chemokine receptor expression on the effector T cells. B. this will guide them to enter the inflamed tissue from the blood.

THE IMMUNOLOGICAL SYNAPSE

Second signals triggered by co-receptors are required for T-cell activation CD28 CD40 CD40L B7 ACTIVATION

Phases of T cell response

Effector T cells

The three types of effector T cell produce distinct sets of effector molecules The three main types of effector T cell are shown, as are the types of target cell with which they interact, and the effector molecules that they make.

Naïve T-cells differentiate into various effector cell types Naive CD4 T cells first respond to peptide:MHC class II complexes by synthesis of IL-2 and proliferation. The progeny cells have the potential to become either TH1 or TH2 cells. Different cytokine environments drive the differentiation of CD4 T cells that make different cytokines and have different functions. The principal cytokines that induce each type of effector T cell are shown in the top panels, the transcription factors that characterize these cell types are shown immediately above the cell, and the cytokines that the differentiated T cells produce are shown underneath. Differentiation of TH1 and TH2 is described in the text. The Treg cells shown here are the regulatory CD4 T cells described in Section 7-13 (p. 203), whose function is to keep the activity of other effector T cells in check and prevent autoimmunity

Key step in Th1 differentiation is the production of IL-12 by Macrophages or DCs that will result in the INF-γ production by the T cells and NK cells.

A key step in Th2 differentiation is the production of IL-4 by Mast cells and eosinophil granulocytes then later the T cells join to produce IL-4.

Absence of IL-4 and INF-γ. A key step in Th17 differentiation is the production of IL-1, IL-6 and IL-23 by DCs + TGFβ. Absence of IL-4 and INF-γ.

A SEGÍTŐ T LIMFOCITA ALPOPULÁCIÓK KÜLÖNBÖZŐ ANTIGÉN PREZENTÁLÓ SEJTEKKEL MŰKÖDNEK EGYÜTT B7 expression  antigen presentation Csíraközpont kialakulása Affinity maturation Isotype switch Memória B sejt képződés Th2 B IL - 4 B7 expression  antigen presentation MHC-II expression  antigen presentation Érett dendritikus sejt Macrophage activation DCMΦ Th1 IFNγ

IL-12 helps Th1 cell differentiation Virus, bacteria, protozoa, fungi DCMΦ CD8+ cytotoxic T cell IL-12 NK cell IL-12 IFNγ Th0 Th1 IL-12 Th2 IL-4 IL-5 IL-10 IL-13 IL-2 IFNγ TNF-β GM-CSF IL-3

IL-10 helps Th2 cell differentiation DC Saját szövet, tumor cell IL-10 Macrophage Th2 IL-4 IL-5 IL-10 IL-13 Th0 IL-10 Th1 IL-2 IFNγ TNF-β TNF-α GM-CSF IL-3 TOLERANCE

The three types of effector T cell produce distinct sets of effector molecules The three main types of effector T cell are shown, as are the types of target cell with which they interact, and the effector molecules that they make.

Release of the clustered granules at the site of cell-cell contact Cytotoxic T cells alignment and delivery of cytotoxins onto a target cell Naïve CD8+ T cell Activated CD8+ cytotoxic T cell, polarization and alignment of lytic granules + cytoplasmic components towards the target cell Release of the clustered granules at the site of cell-cell contact Microtubules (green) Lytic granules (red) As shown in the panels on the left, initial adhesion to a target cell has no effect on the location of the lytic granules (LG) (top panel). Engagement of the T-cell receptor causes the T cell to become polarized: the cortical actin cytoskeleton at the site of contact reorganizes, enabling the microtubule-organizing center (MTOC), the Golgi apparatus (GA), and the lytic granules to align toward the target cell (center panel). Proteins stored in lytic granules are then directed onto the target cell (bottom panel). The photomicrograph in panel a shows an unbound, isolated cytotoxic T cell. The microtubules are stained green and the lytic granules red. Note how the lytic granules are dispersed throughout the T cell. Panel b depicts a cytotoxic T cell bound to a (larger) target cell. The lytic granules are now clustered at the site of cell-cell contact in the bound T cell. The electron micrograph in panel c shows the release of granules from a cytotoxic T cell. Panels a and b courtesy of G. Griffiths. Panel c courtesy of E.R. Podack.

TCR signaling

B cell activation

Phases of B cell response

Lymph node Germinal center (site of intense B cell proliferation) 5. Medullary cords (Macrophage & plasma cell area) Secondary lymphoid follicle Primary Lymphoid follicle B cell zone Artery Paracortex (T cell zone) Vein Afferent lymphatic vessel (Lymph, Ag & cells with captured Ag drained from tissue enters here) 6. Efferent lymphatic vessel

Marginal sinus (phagocytes) Secondary follicle (Ag) Germinal center (GC) B CELLS Afferent lymph Efferent lymph Plasma cell Memory B cell Mature,naive B cell Primary follicle (no Ag) B CELLS High endothelial venule (HEV) T CELLS Collagen capsule T CELLS B CELLS STRUCTURE OF LYMPH NODES

The germinal center Where somatic Hypermutation takes place LZ FDC DZ LZ: Light zone DZ: Dark zone FDC: Follicular dendritic cell

Somatic hypermutation High frequency mutation in the rearranged heavy and light chains V domain genes (at the CDR loops) of immunoglobulin genes in activated B cells. An almost random introduction of single-nucleotide substitutions (point mutations) that results in variant antibodies, some of which have higher affinity for the antigen. 1,000,000 times the ordinary mutation rate of a gene Affinity maturation Increasing the affinity of antigen binding sites of antibodies; 1. Somatic hypermutation and 2. The selection of the B cells with the higher affinity to the antigen to be differentiated into plasma cell. !!! Do not confuse with somatic recombination!!! That is DNA recombination in immunoglobulins and TCRs gene segments during B and T cell development, that encode the variable region polypeptide chain!

BCR signaling