Explain the key differences btwn the primary and secondary immune responses as it pertains to the following parameters:
number of cells pathogen-specific initially responding
speed of response
Type of and timing of pathogen specific Abs produced
threshold of activatoin
Timing of generation of effector T-cells
Timing of cooperation btwn innate and adaptive immunity
attached is slide 3 of PP
What Igs are produced in primary vs secondary immune responses? Compare the affinity of these Igs for antigen.
Primary B-cell responses lead to mostly antibodies that have IgM isotype and low affinity for antigen. Secondary responses produce antibodies that are IgG, IgA of IgE and have high affinity for antigen. Class switching and affinity of antibodies are two main features between primary and secondary B-cell responses. Generating B-cell memory responses is another feature of secondary responses and the isotype switched antibodies with high affinity for antigen are the two properties associated with memory cell formation.
Explain how low affinity IgM B-cells are inhibited from proliferation during secondary responses. State the molecules and receptors involved in this process. Why does this process occur?
IgG dominates during secondary responses
IgG controls IgM levels during secondary immune responses when IgG engages the Fc gamma receptor IIB1(FcγRllB1) on IgM- expressing B-cells. This will ensure that low affinity IgM production is prevented from being produced and IgG expressing memory B-cells are induced to produce high affinity IgG molecules by the antigen.
Attached pic: Note that with each exposure to antigen, less IgM and more IgG is produced. This is why with some vaccines, multiple doses are give-tetanus, hep B.
What cell type is critical for formation of memory B-cells? What signals must B-cells receive from these cells to become memory B-cells?
Where does formation of memory B-cells occur?
Memory B-cell responses require TFH cells as well as antigen:
TFH cells specifically are critical for affinity maturation, isotype switching and for memory cell development.
Typically clones of B-cells with highest affinity are produced after receiving signals from TFH cells (cytokine + CD40 ligand). Therefore memory B-cells are typically ones which possess Ig which have high affinity for antigen TH1 and TH2 are not found in germinal centers and follicles.
Although CD4+ TH1 and TH2 cells are able to induce isotype switching, only Tfh are able to lead to affinity maturation and memory B-cell development.
Memory B-cells do not exist for T-independent antigens.
How does the numer of somatic hypermutations change with secondary immune responses?
When are memory T-cells produced? What is the relative amount of memory cells produced in relation to effector T-cells?
Memory T-cells are produced during encounter with specific peptide antigens (from the pathogens) that are presented by MHC molecules on antigen presenting cells. In addition to effector cells some memory cells are generated during T-cell priming. Effector T-cells outnumber memory T-cells.
What CD isoform do memory T-cells express? What is different about this isoform? How is this different isoform produced?
Memory T cells express an altered CD45 isoform that works more effectively with the T-cell receptor and co-receptors during immune response. Due to alternative splicing which cleaves out segments from CD45RA exons to form CD45R0.
What cytokine is required to induce and maintain memory T-cell survival? Explain the levels of this cytokine receptor on memory T-cells vs effector T-cells.
What cells secrete this cytokine?
IL-7 is required to induce memory T-cell survival. Moreover, IL-7 is important in maintaining memory T-cells when antigen is absent. IL-7 receptors are expressed on naïve T-cells and IL-7 is necessary to maintain survival for the naïve T-cells. As a naïve cell becomes an effector cell, IL-7 receptor expression is decreased. On memory cells the IL-7 receptor is kept at relatively high levels on the surface and IL-7 induces survival and homeostatic turnover of the memory cells.
IL-7 secreted by multiple cells such as stromal cells, effector cells
How are memory B-cell and memory T-cell responses similary? What are the differences between these responses and what is the reason for them?
Memory T-cell responses are like memory B-cell responses. During secondary challenge to antigen, effector T-cell responses have shorter lag time and have a higher magnitude of response. The differences between memory T-cells and memory B-cells are that memory T-cell responses are terminated rapidly following clearance of antigen and affinity of the TCR for peptide antigen does not increase (do not want to undo work of thymus-pos and neg selection of T-cells with exact right affinity).
T-cells are rapidly cleared to avoid chronic inflammation. These cells release an abundace of cytokines and some are cytoxic (CTLs) so it is desirable to quickly clear them out when they are no longer needed.
What are the 2 subsets of memory T-cells?
Central memory T-cells (TCM)
Effector memory T-cells (TEM)
Explain the qualities of central memory T-cells and Effector memory T-cells. Be sure to discuss the differences in location and function of these cels.
Central Memory T-cells (TCM)
• Present in secondary lymphoid organs/tissues
• Have limited effector function
• Low threshold for activation
• High potential for IL-2 production=high potential for proliferation and
• Posses CCR7 (chemokine receptor that tells T-cell to travel to paracortex of LN) and L-selectin. Therefore home to lymphoid tissues
• Able to travel to any inflamed site
• More effector cells over time
Effector Memory T-cells (TEM)
• Present in mucosal layer and mucosal tissue
• Have effector function
• Lack CCR7 and L-selectin