BIOT 307: MOLECULAR IMMUNOLOGY

Cells and OrgansMarch 7-9, 2011

IMMUNE CELLS

• B lymphocytes• T “• NK• Macrophages• Dendritic Cells

Antigen-presenting cells (APCs), non-specific

Antigen Specific

characteristic (See Fig. 2-2)• antigen receptors - B, T, NK• cell surface markers – all• functions - all

NOT SHOWN IN CLASS

TYPES OF IMMUNE CELLS

LYMPH SYSTEM• Multiple functions• Branched • All tissues of body• Lymph vessels & nodes• MALT = digestive, respiratory, genitourinary lymphoid tissue, Peyer’s Patches, tonsils, appendix• Bone marrow – all long bones• Thymus• Spleen

SPLEEN: Secondary Lymphoid Organ

B Cells

GALT

LYMPH NODES

HEMATOPOESIS

DEVELOPMENT OF IMMUNE CELLS

Thymus

Bone Marrow IL1-7, CSF – G, GM, M C-kit ligand

Non-self renewing

<----- differentiation

Red cell

Myeloid/Erythroid progenitor

Granulocytes

Look alikeDNA rearrangements

TH , TC subsetsB cell subsets

Stromal cells = green cords

Bone and Marrow

CELL SURFACE MARKERS

SOME HEMOPOETIC CYTOKINES

FATE AND DEVELOPMENT OF B CELLS

B-CELL DEVELOPMENT

Spleen

Also T-independent activation

Naive

Structural and functional changes

B CELLS

• Move from BM to spleen– Marginal zone– Mature follicular circulating B cells

• Ag stimulation Terminal division into plasma cells Abs

• Transitional B cells– Naive, non-circulating located in spleen's marginal

zone– Long-lived follicular B cells = conventional or B2, IgM+,

IgD+

B CELLS• Function = antibody production• Activated by Ag– TC-dependent and TC-independent

• Produce Ig (IgG, IgA, IgM, IgD, IgE) of unique Ag specificity

• Ag recognized is in native/natural, i.e., undigested state– Protein, Polysaccharide, Glycolipid, Nucleic acids

• B Cell Receptors (BCRs) = membrane-bound Ig (antibody) Ag specific molecules

SPLEEN: Secondary Lymphoid Organ

B Cells

B CELLS• B cell subsets– CD5- = marginal zone B cells

• Spleen• Resting mature B cells• Limited repertoire• Recognize common bacterial Ag

–CD5- = B2 B cells conventional (follicular) • Major B cell• B2 B expresses IgM and IgD• 95% recirculating B cells• From secondary lymphoid organs• Long-lived• TC dependent B cell responses to most protein Ag

B CELLS

• B cell subsets– CD5+ = B1 B cells

• 5% of B cell • expresses IgM • Pleural and peritoneal cavities• Self-renewal outside bone marrow• Limited ability to rearrange limited diversity/repertoire• Recognize common bacterial Ags, e.g., carbohydrate and

lipid• Recognition skewed toward TC-independent Ag• Not memory B cells

B CELL SUBSET COMPARISONJaneway

B CELL: MAJOR SURFACE MOLECULES

• Immunoglobulins

– Clonal selection by Ag

– 1 antigen determinant per B cell

– = major B-cell receptor (BCR) molecule

– Antigen types recognized

• protein, polysaccharide, glycolipid, and nucleic acids

• Undigested or natural state

B CELL: MAJOR SURFACE MOLECULES

• Fc receptors – Fc = constant region of Ig– Modulates events after Ag binds to BCR

• Complement receptors – CR1 (CD-35) and CD2 (CD21) bind certain

complement products– Enable binding of Ag-Ab-complement complexes

• Maturation receptor (CD40)– Binds to CD40 ligand on T cells– Enhances survival and maturation into plasma cells

B CELL: MAJOR SURFACE MOLECULES

• T cell-derived factor receptors– CD80 (BC-7), CD-86 (BC-2) on B cells interact with

CD28 and CTLA-40 on T cells. CD28 and CTLA-40 are regulatory molecules.

– On activated B cells– Bind to corresponding molecules on T cells (TC-

dependent)• MHC proteins (Class I and II)– Ag presentation to T cells– Class II turns B cells into APCs

T CELLS

• Only recognize protein antigen in the form of peptides bound to MHC molecules – MHC restriction

• Protein antigen found on APCs– B cells, macrophages and dendritic cells– Virus-infected cells– Graft cells– Cancer cells

• Activated when T cell receptors (TCRs) on T cells recognize

T CELL FUNCTIONS

1. Regulatory, i.e., modulate activities of– Other T cells– Dendritic cells (DCs)– Macrophages– B cells

T CELL FUNCTIONS

2. Mediate CMI through production of cytokines and chemokinesPromote proliferation/differentiation of T cellsAttract/activate other elements of immune

system:• inflammation, delayed type hypersensitivity (DTH),

resistance to infection by intracellular pathogens

T CELL FUNCTIONS

3. Interact with and destroy target cells– Virus-infected cells– Foreign tissues– Tumor cells

CELLS IN THYMUS

• Maturation – Thymic stromal cells release hormones and

cytokines and express ligands

• CD4 and CD8 αβ T cells CD4+ and CD8+

• γδ TC – T reg– NK– Intraepithelial lymphocytes

• Thymic stromal cells and APCs (macrophages and DCs) MHC recognition of MHC I/II molecules

MATURATION

MORE NOTES FOR PREVIOUS PAGE: Memory T cell, confer long-term immunity. Tregs CD4+CD25+, some of which are generated from the thymus, are thought to suppress CD4+ and CD8+ T cells

B-cell development in the bone marrow: common lymphocyte precursors (CLP) immature B lineage-committed cells (pro-B) Ig heavy chain gene rearrangements in pre-B cell stage -->naïve mature B cells leave bone marrow w/ the IgM receptor secondary lymphoid tissues, where they encounter antigens and are activated; secrete IgM and may isotype switch to IgG. Some differentiate into plasma cells, secreting antigen-specific IgG antibodies essential for long-term immune response.

NOTES FOR PREVIOUS PAGE: Schematic representation of T cell development. T cells originate from the common lymphoid progenitor cells in the bone marrow. They migrate as immature precursor T cells via the bloodstream into the thymus, which they populate as thymocytes. The thymocytes go through a series of maturation steps including distinct changes in the expression of cell surface receptors, such as the CD3 signaling complex (not shown) and the coreceptors CD4 and CD8, and the rearrangement of their antigen receptor (T cell receptor, TCR) genes. More than 98% of the thymocytes die during maturation by apoptosis (†), as they undergo positive selection for their TCR's compatibility with self-major histocompatibility molecules, and negative selection against those T cells that express TCRs reactive to autoantigenic peptides. In humans, the vast majority of peripheral blood T cells expresses TCRs consisting of α and β chains (αβ T cells). A small group of peripheral T cells bears an alternative TCR composed of γ and δ chains (γ/δ T cells). αβ and γδ T cells diverge early in T cell development. Whereas αβ T cells are responsible for the classical helper or cytotoxic T cell responses, the function of the γδ T cells within the immune system is largely unknown. αβ T cells that survive thymic selection lose expression of either CD4 or CD8, increase the level of expression of the TCR, and leave the thymus to form the peripheral T cell repertoire.Skapenko et al. Arthritis Research & Therapy 2005 7(Suppl 2):S4 doi:10.1186/ar1703

Key T-cell Molecules and FunctionsT cell Ag receptor TCR Defines TC

CD4, CD8 TH, TC Divides TC into 2 types

CD40 ligand CD154 Interacts with CD40 on B cells BC activation

TNFR superfamilyCD28 familyadhesion molecs.

Co-stimulatory molecules

IL-1 receptor Helps activate TC

MHC Class I, II

CD45 Signal transduction

THELPER ACTIVATION

• MHC II peptide (antigen) complex on APC binds CD4+ and TCR

proliferation, differentiation Ag-specific effector cell clones

• Type of Ag and APC activate unique cytokine profiles 3 functional TH types– TH1 secrete IFN-γ, IL-2, TNF-β (CMI)– TH2 secrete IL-4, 5, 10, 13 (HI)– TH17 secrete IL-17 (inflammation)

CD4+, THELPER

• Stimulates B cell antibody production• Activates macrophages and TC

• Maintain memory• Main responder to antigens presented by MHC II– CD4 binds directly to region of APC’s MHC II molecule

• Four types based on cytokine secretion and functional activities: TH1, TH2, TH17 and Treg

• 50-75% T cells

CD8+, CYTOXIC (TC)

• Kill virus-infected cells, transplanted tissue, cancer cells

• Two mechanisms:– Bind to cell surface and inject perforin and

granzymes– Bind to Fas ligands apoptosis

CD8+, CYTOXIC (TC)

• Naive TC activation involves – co-stimulation by DCs/cytokines – Proliferate when TCR recognizes foreign

processed (peptide) Ag associated with MHC I (cross-presentation)

• Effector cells secrete IFN-γ • Subsets according to cytokines secreted• Class 1 MHC restricted• 20-40% T cells

TREG

• Suppressor TC • CD4+, CD25+ (IL-2 receptor α chain), FOX P3+

expressing FOXP3 – transcription factor• = 5-10% T cells• Prevent autoimmune disease• Diminish effector responses to cancer and

infections

γδ+ TC

• CD4-, CD8-, CD3+• Function in innate manner• Generate memory• Less TCR diversity but TCR genes rearrange• Recognize phosphorylated microbial molecules

and lipid antigens not presented by MHC – soluble molecules

• Gut mucosa• IFN-γ, THF-α

Continued