11-3-09 Immunological Memory 1. Understand and describe the mechanism of affinity maturation in an antibody response.

B cells with receptors of high affinity are selected to undergo clonal expansion, differentiation, and somatic hypermutation in germinal centers (while B cells with a wide range of affinity bind antigens and become acti ated to produce antibodies of low affinity in the primary antibody response!" It all subse#uent secondary memory responses, antibodies with high affinity will predominate" 2. Memory T cell responses differ from primary T cell responses in a number of important properties. Understand the important properties of primary and memory T cell responses, and name two ways in which they differ. Describe the underlying mechanisms involved in each case. Memory $ cells ha e distinct activation requirements and cell surface proteins that distinguish them from effector $ cells" Moreo er, upon encountering antigen, memory $ cells elicit immune responses much more rapidly and vigorously than effector $ cells" $here are two types of memory $ cells% central memory $ cells and effector memory $ cells" $here are distinct sur i al re#uirements for each cell type% &a' e $ cells% I !", I !1#, and self!$g%M&' (ffector $ cells% do not sur i e for long periods of time Memory $ cells% I !", I !1# (self-)g%M*+ for sur i al but not proliferation! $here are different adhesion molecules for each cell type% (ffector $ cells% lose ++,- and .-selectin, because these molecules function in entering *(/s and are not needed to home into sites of infection side note% only high I !"() 'D* T cells can generate robust memory responses +entral memory $ cells% regain ''(" and !selectin, because central memory $ cells remain in peripheral lymphoid tissues (and need to pass through *(/s! (ffector memory $ cells% lose ++,- and .-selectin because effector memory $ cells stay in the mucosa, but they do e0press ''(#" 1pon restimulation, they di ide faster than central memory $s and differentiate rapidly into effector $ cells, secreting lots of I2&gamma and I.-3" In summary, central memory $ cells express ++,- and remain in lymphoid tissue, while effector memory $ cells do not e0press ++,- and migrate into peripheral tissues in the mucosa" +. Understand the main phenotypic and functional difference between central and effector memory T cells, and plasma and memory , cells. $he $ cells -ffector memory $ cells ((M!% located in the mucosa and therefore do not e0press ++,-" $hey can rapidly mature and differentiate into effector T cells and secrete large amounts of I2&-gamma, I.-3, and I.-4 upon re-e0posure to the same antigen"

'entral memory $ cells (+M!% remain in lymphoid tissue due to the e0pression of ++,-" It ta5es them longer to differentiate into effector $ cells, and they do not secrete as large amounts of cytokines" Moreo er, central memory $s are not yet committed to particular effector lineages" 6nce re-e0posed to the same antigen, the +M lose its CCR7 and differentiate into effector memory $ cells" ) specific subgroup of central memory $ cells called '.(#) home to B cell follicles and provide help for B cells" $hey are considered follicular helper cells"

$he B cells /lasma cells migrate to the bone marrow and continue to produce antibodies from months to years after the antigen has been eradicated" $hey function in pro iding immediate protection" 0riginal antigenic sin refers to how antibodies against the original irus ( irus from the ery first e0posure! tend to suppress the responses of na' e B cells specific for the new epitopes present on a new irus ( irus from subse#uent e0posures!" In other words, a patient who gets his second flu will produce antibodies that are identical to those made during his first flu (the antibodies are based still based on the epitopes of the original irus, e en though the current irus has no el epitopes that a na' e B cell could recogni7e!" Memory cells de elop in the germinal centers following isotype switching, affinity maturation, and somatic hypermutation" 8ubse#uently, they stay in circulation or various tissues but do not migrate to the bone marrow" Memory B cells with higher affinity are selected to undergo further e0pansion and differentiation with each additional round of immuni7ation" 8econdary responses generate a greater amount of antibodies, increased heavy chain class switching, increased affinity maturation, and increased somatic hypermutation" 1. Understand the significance of chemo2ine receptors in cell traffic2ing. ''(" and !selectin are e0pressed on nave $ cells (as well as na' e B cells! to facilitate entry into lymph nodes ia !"s" +hemo5ines e0pressed in lymph nodes bind to receptors on na' e $ cells, enhancing integrin-depndent adhesion and migration through the *(/ .-selectin binds to sulfated carbohydrates (on +933 and :ly+)M-I! on *(/ /!selectin, -!selection, integrins, and chemo2ines secreted at inflammatory sites mediate mo ement of acti ated $ cells from lymph nodes to sites of infection in peripheral tissues" (ffector $ cells migrate to sites of infection using receptors to bind to ligans induced on endothelium by cyto5ines produced during innate immune reactions to microbes $ cells that recogni7e microbial antigens in e0tra ascular tissues are retained at the tissue site by integrin#mediated adhesion to the extracellular matrix" effector $ cells lose .-selectin and ++,- e0pression, and instead e0press 3 $!1 )nd 4$!1 that bind /+)M-1 and I+)M-1, respecti ely (in other words, these new receptors allow for the $ cell t home to the site of infection! 'D1#(0 ma5e effector $ cells more sensiti e to specific antigens

side note% +934,6 is also e0pressed in both central memory and effector memory $ cells

)dditional notes% *ow memory $ cells de elop is still poorly understood" $hee possible models of memory $ cell differentiation ha e been proposed% linear differentiation model bifurcati e differentiation model self-renewing effector model &a' e and memory $ cells demonstrate stem cell#like plasticity" ) na' e $ cell can differentiate into all subtypes of effector and memory $ cells" It is belie ed that asymmetrical di ision of na' e $ cells is responsible for this, where two phenotypically distinct daughter cells can become either short li ed effector $s or long-li ed memory $s" /rotective immunity has four components% plasma cells are the first line of protection, producing neutrali7ing and opsini7ing antibodies effect is short li ed (ffector $ cells 8hort-li ed response that disappears; cells die once antigen is eradicated memory B cells Memory $ cells Both memory B and $ cells function in long#term protecti e immunity, controlling infection and pre enting clinical disease" Maintenance of memory does not re#uire repeated e0posure )cti ated memory $ cells actually 5ill )<cs harboring antigen before they can acti ate na' e $ cells"