B and T cell Memory Bengt Lindbom Adap6ve Immunity BMC D14
Immunity: a historical perspec6ve 430 B.C. Thucydides describes the ongoing plague of Athens:.the same man was never attacked twice 15th century: Chinese and Turks induced immunity deliberately by inserting crusts from smallpox pustules into cuts in the skin. Vaccination! Followed by experiments of Jenner (1798) and Pasteur. Life-long memory (measles outbreak in the isolated community of the Faroe Islands, where immunity to the virus survived 65 years between epidemics) Serological memory for life (circulating antibodies against yellow fever virus detected in people in Virginia, USA, 75 years after an attack of yellow fever.
Mechanisms underlying protec6ve immunity Red = Mechanisms used to clear 1 infection Yellow = Protective immunity
Vaccines Neutralizing an6bodies underlie protec6on conferred by essen6ally all today available vaccines! BCG (Tuberculosis vaccine) seems to be an excep6on: s6mulates Th1 dependent protec6on by macrophages Possible to develop vaccines that s6mulate protec6ve CD8 T cell memory??
Serological memory can provide lifelong protection I. J. Amanna et al. 2007 N Engl J Med Serum antibody half-life estimated to be >1000 years for certain specificities! Compare half-life of IgG molecules in serum: 21 days Antibodies induced by vaccination display much shorter serum half life than those induced by natural infection. Why?
Immunological memory why? Neutralizing an-bodies are transferred from the mother to the immuno-incompetent offspring Serological memory important for survival of the species Perhaps more important than an enhanced response in a primed immuno-competent host..it is important to appreciate, arer all, one can only die once. Zinkernagel, Rolf M. 2002. Current Opinion in Immunology. 14:523
Defini6on of memory A quan-ta-vely and qualita-vely improved response to a previously encountered an6gen Quantity Clonal expansion Quality B cells: Affinity maturation Isotype switching T cells: Lower threshold for activation Polarized and rapid effector functions
Quan6ty T cell precursor frequency for a given antigenic peptide in the naïve repertoire: ~ 10-5 - 10-7 Frequency of virus-specific memory CD8 + T cells can be as high as some percent of the CD8 T cell pool in virus exposed subjects
B cell memory
Peripheral B cell differen6a6on: an6gen- driven B cell development: an6gen-independent Peripheral B cell differen6a6on: An6gen-driven
Major differences between primary (naïve) and secondary (memory) B cell responses
Germinal Centers Affinity maturation T cell zone Long-lived plasma cells Memory B cells GC B cell follicle B220 IgD TCRβ
Germinal centers: affinity matura6on and genera6on of memory B cells & long-lived plasma cells
Transcrip6onal regula6on of memory B versus plasma cell differen6a6on GC B Bcl-6 Weak T cell help Strong T cell help CD40 IL-21 Memory B Bach2 PC Blimp-1
Output from germinal centers Memory B cells (surface Ig positive, resting) - Splenic red pulp, marginal zone - Medullary cords (LN) - Tonsillar epithelium (reticulated crypt epithelium) Long-lived plasma cells (abundant Ab secretion) - Bone marrow - Intestinal mucosa (lamina propria) - Sites of inflammation (inflammatory chemokines)
The bone marrow serves as the major reservoir for long-lived plasma cells
Rapid reac6va6on of memory B cells: direct conversion into plasma cells as well as secondary GC forma6on
Secondary germinal centers: An6body 6ters and affinity increase progressively with the numbers of immuniza6ons
Mechanisms: 1. Second round of BCR diversifica6on and selec6on 2. Selec6ve pressure of pre-exis6ng an6bodies
Summary Germinal centers and CD4 T cells are important for development of B cell memory Characterized by increased number of specific cells, increased Ig (BCR) affinity and isotype switched Ig Serological memory (plasma cells in the bone marrow) can be for life Mechanisms controlling long-term survival of memory B cells and plasma cells largely unknown; memory B cells depend on (tonic?) BCR signaling
T cell memory
Memory B cells diversifica6on and survival of the figest! What about memory T cells? Development of Memory Maintenance of Long-lived Memory
Memory T cells have lower ac6va6on threshold and are pre-programmed
At least two types of memory T cells Effector Memory T cells (T EM cells) Immediate effector func6ons Access to peripheral 6ssues (Inflamed and noninflamed, e.g. skin, intes6nal mucosa and lungs) Central memory T cells (T CM cells) No effector func6ons imprinted Home to lymphoid 6ssues
Central memory T cells and naïve T cells express the same pagern of homing molecules Central memory Naïve Effector memory
Both central and effector memory T cell subsets display an enhanced prolifera6ve recall response, as compared to naïve T cells. Only The effector memory subset produces effector molecules In vitro recall response naïve Central memory Effector memory
Further heterogeneity in memory T cell compartment: Stem cell memory (T SCM ) Central memory (T CM ) Effector memory (T EM ) Tissue resident memory (T RM )
Maintenance of long-term T cell memory Cytokine-driven homeosta6c prolifera6on Contact with self MHC/pep6de (?) Persistence of an6gen?
Role for common gamma chain receptor Cytokine family
T cell memory impaired in the absence of IL-7R signaling Not clear why some ac6vated T cells gain high levels of IL-7R expression during the primary response
IL-7 IL-15 survival proliferation CD8 Memory T IL-7 survival CD4 Memory T
Summary Most effector T cells die but a few survive and become long-lived memory cells Entry into memory T cell pool requires expression of IL-7R Memory T cells display a lower ac6va6on threshold + epigene6c imprin6ng of effector func6on At least two types of memory T cells: central versus effector memory cells (compare memory B cells and plasma cells)
CD8 T cell memory Development of CD8 T cell memory is dependent on CD4 T cell help
1 response Infect with low dose of recombinant Listeria expressing OVA 2 response Wild type vs. CD4-deficient Count # of bacteria and # of OVA-specific CD8 T cells in spleen over time After bacterial clearence, re-infect with high dose of recombinant Listeria expressing OVA Wild type vs. CD4-deficient Count # of bacteria and # of OVA-specific CD8 T cells in spleen
1 infection 2 infection (high dose)
CD8 T cells in CD4 T cell deficient mice fail to expand during secondary infection
Are CD4 T cells required for the imprinting of CD8 T cell memory during the primary response? OR Necessary for an appropriate function of memory CD8 T cells during the recall response?
Thy 1.2 Thy 1.2 wildtype 80 Days CD4-deficient CD8 CD8 CD8 Thy 1.2 CD8 CD8 CD8 Thy 1.2 Thy 1.1 CD8 Thy 1.1 CD8 Non-immune wild type recipient mice
IFN-γ production Thy 1.1 Transferred cells ( memory ) Endogenous cells (naïve) CD8 T cells primed In the absence of CD4 T cells fail to expand in secondary response when CD4 T cells are present CD4 T cells required for the generation of CD8 T cell memory
Primary CD8 T cell responses CD4 T cell-independent CD4 T cell-dependent 2. CD8 T 2. CD8 T DC DC 1. TLRs Pathogens LPS CpG dsrna 1. CD4 T CD40 CD40L
Generation of CD8 T cell memory CD4 T cell-dependent 2. CD8 T DC 1. CD40 CD40L DC CD8 T CD40 CD40L CD4 T CD4 T Compare with B cell memory!!
Summary Primary CD8 T cell responses can be CD4 T cell independent Development of CD8 T cell memory is dependent on CD4 T cells Compare similar role for CD4 T cells in forma6on of B and CD8 T cell memory
Implica6ons Vaccina6on Strategies to generate the appropriate memory compartment How is long-term memory obtained? Allergy and autoimmune disease: Reversal of memory phenotypes