12_Immunological_Memory_Szalai2023.pptx

Immunological Memory Molecules to People Course 2022 Dr. Gabor Szalai Email: [email protected] Learning objectives 1. Compare and contrast naïve, effector and memory B & T cells 2. Describe the process of maintaining a memory cell population 3. Compare and contrast primary and secondary immune...

Immunological Memory Molecules to People Course 2022 Dr. Gabor Szalai Email: [email protected] Learning objectives 1. Compare and contrast naïve, effector and memory B & T cells 2. Describe the process of maintaining a memory cell population 3. Compare and contrast primary and secondary immune responses with respect to both B and T cells 4. Describe the mechanism that ensures that low affinity antibody is not produced in secondary responses 5. Explain the concept of original antigenic sin 6. Compare and contrast the various memory T cell subsets Overview • Successful primary immune response achieves two goals – effector cells/molecules end an infection – create reserve of memory B and T cells • secondary immune response is faster/more potent; infections cleared before harm to host occurs 1. How is immunological memory developed during the latter stages of the primary immune response? 2. How is immunological memory used to develop a secondary immune response to subsequent infections by the same pathogen? Primary immune response Ab formed during a 1° immune response prevent re-infection • Successful 1° immune response to infection: – protective immunity • high levels of high-affinity specific Ab in blood, lymph, mucosal surfaces (many months) • plasma cells in the marrow or beneath mucosal surfaces maintain high Ab levels – prevents recurrence of seasonal diseases • immediate coating by preexisting IgA or IgG Long-lived plasma cells Low levels of pathogen-specific Ab are maintained by long-lived plasma cells • Most plasma cells are short-lived – following infection, gradual decline (~1 year) in pathogen-specific Ab levels due to: • loss of physical and chemical (IL-6) interactions with stromal cells • induction of apoptosis • Long-lived plasma cells remain in bone marrow – continuous secretion of high-affinity Ab • one component of host immunological memory of a pathogen Long-lived memory T and B cells Immunological memory is sustained by long-lived memory T and B cells • • • Goal 1 of 1° immune response: subdue ongoing infection that is outrunning innate immunity Goal 2 of 1° immune response: ensure that future invasions by same infection do not cause illness – mediated by memory T cells and memory B cells during 2° immune responses – 2nd and 3rd components of immunological memory All memory cell types exist – – – • • memory CD8 T cells memory CD4 T cells (Tfh, Th1, Th2, Th17) memory B cells Beginning of immune response: effector cells End of immune response: memory cell Long-lived memory T and B cells • Advantages of memory cells over naïve lymphocytes – – – more abundant more easily activated (like effector cells) memory B cells: isotype switched, high affinity (can continue these processes) • can continue isotype switching/affinity maturation during subsequent infections (produce better memory cells) • All memory responses = “secondary” responses • Lymphocytes require regular antigenic stimulation to survive – • die by apoptosis without survival signals Memory cells do not have this restriction – – population survives via ongoing proliferation survival/proliferation depends on IL-7/IL-15 stimulation Long-lived memory T and B cells Changes to Ag receptor distinguish naïve, effector and memory B cells • Memory B cells easier to distinguish from naïve B cells compared to memory T cells and naïve T cells • Distinguishing features of memory B cells: – – receptor is isotype switched/affinity-matured express CD27 Pathogen-specific memory B cells are more abundant than naïve B cells • • 10-100x more Ag-specific memory B cells for 2° responses Memory B cells: derived from clones with highest affinity during 1° immune response Secondary immune response Cell activation in a 2° response is similar and different to/from a 1° response • Activation of naïve Agspecific B cells is suppressed during 2° responses Why? • Immune complexes (Ag + Ab) bind to FcγRIIB1 (inhibitory) on naïve B cells to suppress them Secondary immune response Memory B cell responses are similar to and different from 1° responses • SIMILAR B cell response begins in the 2° lymphoid tissue at the interface of B-cell and T-cell zones – – • • memory B cells that have endocytosed Ag present peptide:MHC II complexes to their cognate Tfh cells which drives proliferation/activation of both cell types competition for binding of Ag drives the selective activation of B cells with highest affinity BCRs for Ag • average affinity of Ab made in the 2° response are well above those made in the 1° response DIFFERENT Due to higher affinity BCRs, memory B cells are more sensitive to Ag, and their response is quicker than that of naïve cells Memory B cells express more MHC II and co-stimulatory molecules making their interactions with Tfh cells more efficient – – smaller pathogen population triggers a B-cell response memory B cells take less time to differentiate into plasma cells Note log scale! Secondary immune response Immunological memory to pathogens that undergo antigenic drift is gradually eroded • Good strategy: suppress naïve B cell activation during 2° response to a pathogen – • Memory responses direct Ab to be made only against epitopes shared between new and original strains – – • has drawbacks: antigenic drift disease caused by emerging new strains becomes increasingly severe imprint made by original strain broken only upon infection with strain that lacks all B cell epitopes of original Original antigenic sin: phenomenon whereby the first pathogen strain to infect a person limits future responses to other strains Secondary immune response Memory T cell responses are similar to and different from 1° responses SIMILAR • Activation in 2° lymphoid tissues by DCs: ONLY FOR SOME DIFFERENT • Circulation in peripheral tissues: ONLY FOR SOME – – • allows activation directly at infection sites by APCs memory T cells do not require co-stimulation through CD28 Increases speed of 2° response by T cells Long-lived memory T cells Cell surface markers distinguish memory, effector and naïve T cells • Differences in gene expression exist between naïve, effector and memory T cells – • cell-surface proteins; various effector molecules CD45RA, CD45RO, L-selectin (CD62L), CCR7 used to distinguish T cell subsets – IL-7 receptor (essential for renewal/survival of memory cells): also be used Long-lived memory T and B cells Two types of memory T cell recognize Ag in different tissues • Two subsets of memory T cells defined – – – • • • central memory T cells (TCM): (CD45RA hi; CD62L hi; CCR7 hi) IL-2 production, cellular proliferation, differentiation into effector cells effector memory T cells (TEM): (CD45RA lo & hi;subsets: CD62L lo; CCR7 -lo) two CD45RA (TEM) and CD45RA+ (TEMRA = “terminally differentiated”) highly heterogeneous and differentiated – CD8, Th1, Th2, Th17, etc. quickly differentiate into effector cells that respond immediately to infections – complements TCM activation (slower; generates more effector T cells) Long-lived memory T and B cells Pathogen-specific memory T cells are more abundant than naïve T cells • Viral infections can induce production of massive numbers of effector CD8 T cells – • each Ag-activated naïve T cell can give rise to 50,000 CTLs After virus clearance, ~95% of CTLs die by apoptosis – – remaining 5% = memory CD8 T cell population • express IL-7R 100-1000x more memory T cells than naïve cells from 1° response Summary Thank you for your attention!