Chapter 1 part 2, slides 35 to the end

1. Chapter 1 part 2, slides 35 to the end

2. Antigen binding site Immunoglobulins (i.e., antibodies) Constant regions Variable regions

3. What about the TCR effector function ? Cell plasma membrane

4. Immunoglobulin and TCR variable region genes are made from gene segments bygene rearrangements. This contributes to the building of the antigen-recognition repertoire of B and T cells. Other mechanisms also contribute to the generation of diversity in the antigen-binding receptors

5. The generation of diversity(i.e., the generation of a diverse antigen-binding repertoire for Ab and TCRs) • Gene rearrangements (combinatorial diversity) • Junctional diversity • Light chain-heavy chain pairing (L-H pairing) (combinatorial diversity) • For B cells only, somatic hypermutation

6. What is achieved by gene rearrangements and other mechanisms for the generation of diversity? 1. Relatively few gene segments can combine to make millions of different receptors (large repertoire) (i.e., 100s of gene segments can be assembled to make millions of variable regions for Igs and TCRs). 2. Different cells can have different antigen receptors. 3. Somatic progeny of a cell with a gene rearrangement will inherit the gene rearrangement and thus inherit the antigen recognition specificity of the parent cell.

7. Clonal selection solves the problem of a repertoire that is too large to be fully functional all the time. It is also the basis of immunological memory and tolerance (self/non-self discrimination). The down-side is that it is slower to respond than innate immunity because lymphocytes must divide to produce enough cells to mount an effective response and differentiate into effector cells. Antigen-activated, dividing lymphocytes are lymphoblasts. Lymphoblasts divide every 6-8-12 hours. Eventually (usually 4-7 days), lymphoblasts will differentiate into effectors and memory cells. B cells  plasma cells T cells  active CTL (killers), TH1 or TH2 cells also B and T cells  memory B and T cells

8. Effector cells have limited life-spans (maybe 7 days) and clonal expansion will continue only in the presence of antigen. Therefore, when antigen is gone 1. Activation (division and differentiation) ends. 2. Effectors die off and are not replaced, or lose effector function 3. The response subsides Adaptive immune responses are limited by the concentration of antigens. As long as antigen is present, the response continues. When antigen is gone, the response subsides; however, memory cells remain.

9. Antigens are the molecules recognized (bound) in an adaptive immune response. Epitopesare the sites where the antigen receptors bind to the antigen

10. Antigen recognition by antibodies Antigen recognition by TCRs processing presentation Antibody binds the surface of an antigen; usually the antigen is in its native configuration TCR bind antigen that has been processed (cut in to small pieces) and presented on the surface of a cell by MHC (note: the antigen presenting cell is a self cell, NOT the surface of a foreign cell)

11. Plasma cell TH2 activation, for example B cell activation, for example (Armed effector T cell) Memory B cell Proliferation and differentiation of the B cell to acquire effector function The two signal model for lymphocyte activation(antigen alone is insufficient) Antigen+MHC TCR (Mature dendritic cell) (Mature naive T cell) Proliferation and differentiation of the T cell to acquire effector function Signal 1 comes from recognition of antigenSignal 2 comes from another (activated) cells

12. Professional antigen presenting cells (APC) Professional antigen presenting cells Usually the targets of certain armed effector T cells Usually to activate certain T cells

13. Typical primary and secondary antibody responses

14. Primary response (primary immunization) as compared to a secondary response is relatively: slow; 4-7days to detect specific antibody production small amount of antibody (low concentration of antibody) low affinity antibody IgM first, IgG second (equal amounts of IgM and IgG) Secondary response (secondary immunization or booster immunization) as compared to a primary response is relatively: fast; 2-4 day to detect specific antibody production large amounts of antibody high affinity antibody mostly IgG

15. Often, a secondary (memory) response is so fast and effective in removing antigens (pathogens), there are few or no symptoms detected by the infected individual (protective immunity). Secondary responses are the reason we do not get certain infectious diseases more than once. Secondary responses also explain why vaccinations work. For vaccinations, instead of immunizing with something that makes you sick, a vaccine contains antigens that are expressed on the pathogen but the vaccine is usually not pathogenic (e.g., live organism that is not pathogenic (attenuated), dead organism, purified protein, others).

16. Antigen recognitions and effector mechanisms of adaptive immunity Protection is generally provided by Antibody T cellsT cells (antibody when extracellular) Antibody

17. Antibody-mediated effector mechanisms macrophage Humoral immunity:the immunity mediated by antibodies Different Ig isotypes (classes) provide for different functions. Neutralization works for many toxinsvirusesbacteria Also, different isotypes have different distributions [blood, secretions (mucus, saliva, tears, milk), cross the placenta].

18. TH2 cells control (activate) B cells and thus control Humoral Immunity. TH1 and CTLs control/conduct Cell Mediated Immunity Cell-mediated Immunity (CMI)TH1 and CTL deal with intracellular (inside a cell) pathogens. Intracellular pathogens (some bacteria and all viruses) are found in vesicles or in the cytoplasm. Vesicular and cytoplasmic pathogens are usually dealt with differently. Generally, TH1 forvesicular antigens and CTLs for cytoplasmic antigens

19. Effector CTL CTLs kill cells with cytoplasmic viruses or other foreign material CTLs have CD8 on their surface and are sometimes referred to as CD8+ T cells.

20. Effector TH1 TH1 T cells are sometimes referred to as inflammatory T cells cytokines TH1 and TH2 T cells have CD4 on their surface and are sometimes referred to as CD4+ T cells.

21. TH2 cell “help” B cells Plasma cell B cell activation, for example Memory B cell Clonal selection for B cell Effector TH2 Clonal selection for TH2 cell activation TH2 (Mature dendritic cell) (Mature naiveTH2 cell) (Armed effector TH2 cell) Activation (proliferation and differentiation) of the T cell to effector function Activation (proliferation and differentiation) of the B cell to effector function TH2 cells are sometimes referred to as helper T cells

22. CTL deal with antigens in the cytoplasm by killing the cells that present the antigen. TH1 deals mostly with antigen in macrophage that have phagocytized the antigens so that the antigens are in vesicles. TH1 cells activate these macrophages. Activated macrophages are more aggressive in killing phagocytized material and they release toxic compounds into the local environment. TH2 deals with antigens that were bound to a B cell’s BCRs (extracellular antigens) and internalized (into vesicles). They activate B cells for antibody secretion. For antigens to be recognized by T cells, the antigen must get into a cell, be processed into peptides and presented in association with MHC proteins (see next slide)

23. T cells recognize foreign antigen as peptides bound to proteins encoded in the major histocompatibility complex (MHC) Outside of the cell Inside of the cell MHC is polymorphic (lots of allelic variants)

24. CTL deal with antigens in the cytoplasm TH1 deals mostly with antigen that have been phagocytized by macrophage and thus in antigens in cytoplasmic vesicles TH2 deals with antigens that were bound to BCRs and internalized (in vesicles) the by B cells • For antigens to be recognized by CTLs, they must be presented in association with MHC class I (i.e., cytoplasmic antigens are associated with MHC class I). • For antigens to be recognized by TH1 or TH2, they must be presented in association with MHC class II (i.e., vesicular antigens are associated with MHC class II).

25. T cell T cell T cell peptide TCR MHC APC APC Antibodies bind native antigens (antigens in the configuration they have in nature) TCRs (T cells) bind to the combination of foreign peptide* and MHC. TCRs (T cells) cannot bind foreign peptide alone nor MHC alone. *derived from foreign protein by antigen-processing TCR binding? Yes No No

26. MHC class I gets its peptides from the cytoplasm (i.e., proteins synthesized in the cell) peptides ProteinsribosomemRNA DNA Some cytoplasmic proteins (both foreign and self proteins) are chopped into peptides (frame 2) and transported into the ER (frame 3) MHC class I peptide peptide All nucleated cells are doing this all the time with all types of proteins, not just viral proteins ER

27. = peptide MHC class II macrophage This peptide was derived from this antigen. Thus, for B cells there is a relationship between the specificity of the B cell’s BCR and the peptide presented by MHC class II B cell MHC class II gets its peptides from the proteins transported into the cellular vesicles from the outside (i.e., proteins synthesized outside of the cell) MHC class II

28. For antigens to be recognized by CTLs, they must be presented in association with MHC class I. For antigens to be recognized by TH1 or TH2, they must be presented in association with MHC class II. Therefore, CTLs are interested in proteins synthesized inside a cell whereas TH1 and TH2 are interested in proteins that were synthesized outside of a cell but were brought into the cell in vesicles Why is that important to the immune system?

29. CD8 is a transmembrane protein found on CTLs and is a co-receptor for MHC I (the TCR and CD8 are co-receptors for MHC). Unlike the TCR CD8 is not a receptor for the peptide, too.

30. cytokines CD4 T cell (TH1 and TH2) recognize antigens presented in association with MHC class II Inflammatory T cell TH2 (Signal 2) (Signal 2) CD4 is a transmembrane protein found on TH1 and TH2 cells and is a co-receptor (along with the TCR) for MHC II Note error in book drawing of MHC II

31. Subacute sclerosing panencephilitis (SSPE)