T-CELL MEMORY Central Effector

Immunological memory Inhabitants: 46 000 Area: 1400 km2 1781: Measles epidemic in the Faroe Islands No measles for 65 years 1846: Measles epidemic Those individuals, who were older than 65 years and were infected in 1781 did not became sick, but some elderly people got the infection Life-long protection can be induced against some viruses Presence of the virus is not needed for the maintenance of immunological memeory

DEVELOPMENT OF CELLULAR MEMORY Negative regulation of the immune system AICD Activation Induced Cell Death DIFFERENTIATION Naive lymphocytes Memory Az antigen-specific cell number Secunder effector cells Primary effector cells EXPANSION AICD MEMORY Days

Presence of specific antibodies during primary and secondary immune responses protects against repeated infections A successful primary immune response eliminates the pathogen and results in long-lasting immunological memory Antibodies produced during the primary immune response protect against re-infection by neutralization and opsonization.

Both effector B and T cells and memory B and T cells are produced during a primary immune response

Both antibodies and T memory cells specific to vaccinia virus are Detectable Decades after vaccination Specific antibody titer drops to 0.1-1% of the maximunm within a year. Number of memory B-cells is 10%-of the Max. and stays constant over many years The number of memory T-cells also stays constant over decades Specific anti-vaccinia antibodies continue to be made for as long as 75 years after the last exposure to vaccinia virus, the smallpox surrogate that is used for vaccination (top panel). The numbers represent international units (IU) of antibody, a standardized way of measuring an antibody response. Many vaccinated individuals retain populations of vaccinia-specific CD4 T cells and CD8 T cells (bottom panel). Only small differences are observed for individuals who received one (blue bars) or two (pink bars) vaccinations. Courtesy of Mark Slifka.

Comparison of the B-cell populations that participate in the primary and secondary adaptive immune responses

The amount and affinity of antibody increase after successive immunizations with the same antigen

IgG antibody suppresses the activation of naive B cells by cross-linking the B-cell receptor and FcγRIIB1 on the B-cell surface 9

Passive immunization with anti-Rhesus antigen IgG prevents hemolytic anemia of the newborn 10

Highly mutable viruses such as influenza gradually escape from immunological memory without stimulating a compensatory immune response 11

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Memory CD4 T cells express an altered CD45 isoform that works more effectively with the T-cell receptor and co-receptors 13

PERIPHERAL LYMPHOID ORGANS Naive T Effector T AICD Cytokines/cytotoxicity Central memory T Effector T Cytokines/cytotoxicity PERIPHERAL LYMPHOID ORGANS PERIPHERAL TISSUES Skin dermis, gut lamina propria, alveolar space Tissue-specific migration Effector memory T Effector T Cytokines/cytotoxicity ANTIGEN/ SITE OF INFLAMMATION

T-cells differentiate into central and effector memory cells

Tissue resident memory cells

CYTOTOXIC MEMORY T LYMPHOCYTES PRODUCTION OF EFFECTOR MOLECULES Tissue effector memory T cells Lymphoid central memory T cells Resting Activated Resting Activated Proliferation Cytotoxicity

IMMUNOLOGICAL EXPERIENCE AGE THYMUS PERIPHERY M E O R Y N A I V E IMMUNOLOGICAL EXPERIENCE

Memory T cell frequency in the blood is a marked underestimate of the total frequency and numbers of memory T cells in the whole body. Estimates of the number of T cells in human tissues are 2 × 1010 in the skin,17, 1 × 1010 in the lungs18, 3 × 1010 in the intestines and 20 × 1010 in lymphoid tissues (that is, the spleen, the lymph nodes and the bone marrow). Therefore, peripheral blood T cells (5–10 × 109 in human blood) represent only 2–2.5% of the total T cell complement in the body, and memory T cells represent the predominant T cell subset in mucosal sites, skin, spleen and bone marrow Donna L. Farber1,2, Naomi A. Yudanin1 and Nicholas P. Restifo NRI 2014 p24