Az immunológiai memória kialakulása és fenntartása

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1 Az immunológiai memória kialakulása és fenntartása

2 ‘The same man was never attacked twice’
Thucydides, a pestisről írta Athénben, 430 BC ‘of the many aged people still living on the Faroes who had had measles in 1781, not one was attacked a second time’ Ludvig Panum a kanyarójárvány kitörését vizsgálta a Faroe szigeteken 1846-ban. the old Roman word ‘immunitas’ meaning protection from taxation was adopted to describe this protection from disease.

3 IMMUNOLÓGIAI MEMÓRIA Faroe szigetek- kanyaró járvány: 1781, 1846: %, idősek nem  Vírus specifikus immunitás 65 évig fennállt! Vírus túlélés az agyban? Ludwig Panum ( ): hosszú idejű immunitás nem kell újabb vírus fertőzés hozzá i.e pestis : hasonló megfigyelés, sárgaláz (75 évvel a fertőzés után vírus specifikus ellenanyagokat találtak a vérben), polio etc. Az immunrendszer hosszú ideig képes emlékezni az antigénre  antigén-specifikus memória sejtek Védőoltások

4 Az immunológiai memória kialakulása – B-sejtek
Nyirokcsomó, germinális centrum: a memória a primer GC-ben alakul ki CD40 – CD154 (CD40 ligand) szerepe  A memória kialakulásának 4 fázisa:  1. Indukció: klonális szaporodás szomatikus mutáció receptor editing pozitív szelekció, affinitás érés 2. Fenntartása a GC után: visszatérés a GC ciklusba, ellenanyag szekretáló memória sejtek, nem szekretáló prekurzorok 3. Válasz a második ag ingerre - affinitás érett sejtek nagy számban,  hatékony 4. A memória kompartment fenntartása - a nem szekretáló memória sejtek depléciója akadályozott - szekretáló lesz - a hosszú életû plazmasejetek nem proliferálnak ag hatására, - a nem szekretálók: antigén processing, prezentáció

5 Helper T sejtek által szabályozott B sejt differenciáció
Helper-T-cell regulated B-cell differentiation. Phase I begins at the site of infection with acute inflammation that leads to the activation and emigration of DCs to the T-cell zones of the lymph nodes that drain the area of tissue. Antigen uptake, processing and presentation within the context of MHC II allows the activated DCs to contact and trigger naı¨ve Th cells expressing specific T-cell receptor (TCR) and initiating immune synapse I (Synapse I). B cells have the capacity to recognize soluble protein antigen; however, they are more efficiently activated by cell-bound antigen and may also initiate an immune synapse with an activated antigen-bearing DC. Following clonal expansion, antigen-activated Th cells migrate to the T–B borders of the lymph node to initiate cognate contact with activated antigen-specific B cells. Phase II begins with immune synapse II formation (Synapse II) between these antigen-specific Th and B cells. Synapse II drives a major bifurcation in B-cell differentiation to either short-lived plasma-cell production, which progresses in the T-cell areas, or movement into the follicular areas and the formation of secondary lymphoid follicles. Phase III begins with the polarization of secondary follicles into light-zone and dark-zone regions of activity that typify the GC reaction. This dynamic cycle of activity involves clonal expansion, SHM of the BCR, antigen-specific selection for high affinity variants and then export of memory B cells. These memory B cells can either differentiate into long-lived plasma cells, or remain as non-secreting precursors for antigen recall. Synapse III interactions involve antigen-specific GC Th cells and GC B cells and are proposed to play a critical regulatory role in these late-stage B-cell developmental decisions. I. fázis: az infekció helyén kezdődik, akut gyulladás alakul ki, DC aktiválódnak és a nyirokcsomók T sejtes zónáiba vándorolnak. Ag felvétel prezentáció T sejteknek MHCII+, naív T sejtek aktiválása. I.Szinapszis II. fázis: Aktivált, klonális szaporodáson átesett T sejtek a T/B határterületre vándorolnak. Antigénnel találkozott T és B sejtek között: II. Szinapszis III. fázis: másodlagos follikulusok polarizálódása sötét és világos zónára. Klonális szaporodás, SHM, nagy affinitású receptorral rendelkező sejtek pozitív szelekciója, memória sejtek kialakulása, exportálása. hosszú életű plazmasejtek és nem szekretáló prekurzorok GC TH – GC B: III.Szinapszis

6 Memória B sejtek differenciálódása
IV.Fázis, IV.Szinapszis: MemB+MemTh Különböző fenotípus Memória T helper sejtek Memory B-cell differentiation. At least two phenotypically-distinct types of non-secreting memory B cells clonally expand in response to antigenrecall, together with a rapid and massive production of antigen-specific plasma cells (B220ţ/CD138ţ antigen-binding). B220ţCD138 antigen binding cells demonstrate greater proliferative capacity but lower differentiative potential than their B220CD138 counterparts over five days afteradoptive transfer and antigen re-challenge. These experiments also indicate a parent-progeny relationship between the two memory B-cell subsets,as displayed above. Antigen was required for responsiveness of both memory B-cell subsets; however, the requirement for memory Th cells for eachsubset was not tested, as it was provided in all cases. Memory B-cell differentiation is generally regarded to be memory-Th-cell regulated, suggestingthat the formation of immune synapse IV is a critical checkpoint in Phase IV of TD immune responsiveness. Nem szekretáló memória sejtek két populációja A memória B sejtek differenciálódása a memória T sejtektől függ. Ezért a IV. fázisban a IV. szinapszisnak kritikus jelentősége van a T dependens immunválasz során

7 A másodlagos válasz során a memória B sejtekből elsősorban plazmasejtek képződnek (5x) míg az elsődleges válasz több nem differenciálódott B blaszt sejtet eredményez

8 Hosszú életű plazmasejtek: az állandó ellenanyag termelés fenntartása.
 Mechanizmus antigén stimuláció kérdés ismételt patogén állandó inger inger ellenanyagszint fenntartása Infekció kis mértékû krónikus   immunokomplexek az FDC-n FDC féléletidõ   keresztreakció a környezeti és saját antigénekkel   idiotipus hálózat szabályozás? HOSSZÚ ÉLETÛ  PLAZMASEJTEK (Élettartam: néhány hónap, évek)

9 A hosszú életű plazmasejtek
Az ellenanyag termelés kinetikája a vakcinációt követően (ELISPOT mérés) Kezdeti válasz: lép rövid életű plazmasejtjei Késői válasz: az ellenanyag termelő sejtek 80-90%-a a csontvelőben található

10 Rövid életidejű plazmasejtek
kialakulásához nincs szükség germinális centrumra Van izotípus váltás, de nincs SHM Germinális centrum terméke, főleg csontvelőben Nagy affinitású ellenanyag élethosszig

11 A CD40L irányítja a GC B sejtek differenciálódását a memóriasejtek felé
citokinek CD20- CD38+ CD40L - CD20+ CD38+ citokinek IL2, IL-10 Memória sejt Plazmasejt CD20++ CD38- IL-2, IL-10 GC B B blast CD40L, +

12 Az FcgRIIb feltételezett szerepe a B-sejtes memória kialakulásában
Kompetíció BCR és az AFC által termelt ellenanyag között az antigénhez való hozzáférésért Kis affinitás: apoptózis, közepes affinitás - GC, nagy affinitás + FcgRIIb jel a memória sejt felé történő differenciálódást segíti

13 A B sejtes memória kialakulása az antigénre adott válaszban
Recirkuláló memória ? The formation of B-cell memory in response to antigen. a | After activation by antigen, mature naive B cells (which are located in B-cell follicles in secondary lymphoid organs) migrate to the edge of the follicles, where they receive help from cognate T cells. If the B cells express the appropriate molecules, such as a combination of B-cell lymphoma 6 (BCL-6), inducible T-cell co-stimulator ligand (ICOSL), CD40 and B-lymphocyte-induced maturation protein 1 (BLIMP1), the interaction of the B cells and T cells leads to the formation of short-lived plasma cells and to the establishment of germinal centres in the follicles. In the germinal centre, proliferating antigen-specific B cells (known as centroblasts) are localized at one pole (the dark zone), whereas their non-proliferating immunoglobulin-expressing counterparts (known as centrocytes) localize at the other pole (the light zone). Centrocytes and centroblasts cycle within the germinal centre in a chemokine-driven process. Centrocytes can differentiate into memory B cells or plasma cells, or undergo apoptosis if they fail to receive an antigen-mediated survival signal. Although expression of BLIMP1 is crucial for the formation of plasma cells, the factors that control memory B-cell formation are less well defined. Memory B cells recirculate in the periphery, whereas germinal-centre-derived plasma cells accumulate preferentially in the bone marrow. b | B1b cells can also generate memory B cells in response to T-cell-independent antigens. Exposure to antigen leads to the formation of plasma cells and to the clonal expansion and persistence of antigen-specific memory B1b cells with a phenotype that is indistinguishable from that of naive B1b cells. Conventional B cells have also been shown to be able to give rise to memory B cells in response to T-cell-independent antigens.

14 A memória B sejtek és plazmasejtek kialakulásának modellje a primer immnuválasz során a germinális centrumban A memóriasejtek kompetíciója a túlélésért Figure 2 | A model for the generation of memory B cells and plasma cells in germinal centres during a primary immune response. Cells emigrate from the germinal centre throughout the immune response, as either plasma cells or memory B cells. Under the influence of B-cell receptor (BCR) stimulation, centrocytes with high affinity for antigen differentiate preferentially, but not exclusively, into plasma cells. These plasma cells migrate through the blood, and they accumulate in the bone marrow if they gain access to a survival niche. By contrast, memory B cells that emigrate from the germinal centre constitute a random sampling of centrocytes with various affinities. The size of the memory B-cell pool is finite, so the survival of memory B cells is competitive. Prolonged survival in the germinal centre, which correlates with increased affinity for antigen, improves the competitiveness — also known as the fitness — of the memory B-cell emigrants and, consequently, their representation in the ultimate memory B-cell population. Increasing intensity of colour corresponds to increasing affinity and fitness. VERSENGÉS A TÚLÉLÉSÉRT Prolonged survival in the germinal centre, which correlates with increased affinity for antigen, improves the competitiveness — also known as the fitness — of the memory B-cell emigrants and, consequently, their representation in the ultimate memory B-cell population. Increasing intensity of colour corresponds to increasing affinity and fitness.

15 A plazmasejtek homeosztázisának lehetséges szabályozása az élőhelyek hozzáférhetősége által
Possible regulation of plasma cell homeostasis by survival niches. Probably recruited by the chemokine receptors indicated in bold, plasma cells formed in secondary lymphoid tissues such as spleen and Peyer’s patches migrate into lamina propria, bone marrow or inflamed tissue. Here, their survival depends on the availability of factors provided in a limited number of survival niches. The relatively high numbers of plasma cells competing for survival niches that are present in mucosa-associated tissues result in tough competition conditions and in consequence in the observed short average lifetimes of plasma cells in the lamina propria. The short half-life of plasma cells outside survival niches is probably due to the lack of specific survival signals; however, active elimination can not be excluded. Az élőhelyek száma korlátozott Az élőhelyeken kívül rövid életidő: nincsenek túlélést segítő szignálok aktív elimináció (?)

16 Összefüggés a plazmasejtek migrációja és túlélő képessége között:
CCR7 elvesztése, CXCR4 expresszió  megváltozott kemokin érzékenység CXCR4 : plazma sejt homeosztázis a csontvelőben CXCR3: gyulladásos szövetekbe irányít CCR9: lamina propriába irányít A jel erőssége: IgG erősebb jelet közvetít , mint IgM több IgG termelő plazmasejt túlélést elősegíti NZB/W egerek: nincs több plazmasejt a csontvelőben, DE: folyamatos plazmasejt utánpótlás + több túlélő hely gyulladásos szövetekben, pl. vese Autoimmun memória: A plazmasejtek hosszú élete következtében terápiára ellenálló, fennmaradó auto-ellenanyag termelés. Terápia: ezek eltávolítása Plazmasejtek homeosztázisa: amíg a patogén jelen van –erős kompetíció az immunválasz során keletkező plazmasejtek közül a későbbieknek több esélyük van a túlélésre-kevesebb a kompetíciós nyomás. Gyulladásos szövetben további élőhelyek.

17 Hosszú életű plazmasejtek a csontvelőben
A csíraközpontból kikerülő plazmasejtek elveszítik a CXCR5-t és fokozzák a CXCR4 kifejeződését csontvelőbe vándorolnak, ahol a CXCL12 ligandum termelődik integrin, poliszaharidok erősítik a plazmasejtek csontvelőben tartását. Stimulálják a stromasejteket IL-6 szekrécióra. BCMA+IL-6: Túlélő jelek Figure 6 | Long-lived plasma cells in the bone marrow.   Post-germinal-centre plasma cells, which express somatically mutated, class-switched immunoglobulin, lose expression of CXC-chemokine receptor 5 (CXCR5), facilitating their exit from the germinal centre. These cells then increase their expression of CXCR4, which helps them to home to the bone marrow, where stromal cells produce high amounts of CXC-chemokine ligand 12 (CXCL12). Endothelial-cell selectin (E-selectin) and vascular cell-adhesion molecule 1 (VCAM1) expressed at the surface of bone-marrow stromal cells are important for the retention of plasma cells in the bone marrow, through association with polysaccharides and integrins expressed at the surface of the plasma cells. Plasma cells induce the stromal cells to produce interleukin-6 (IL-6). B-cell-activating factor (BAFF), probably produced by macrophages or dendritic cells, activates the receptor B-cell maturation antigen (BCMA) and, together with IL-6, provides crucial survival signals to the plasma cells. BLIMP1, B-lymphocyte-induced maturation protein 1; IL-6R, IL-6 receptor; SDC1, syndecan; XBP1, X-box-binding protein 1.

18 A csontvelő felépítése
Mezenchimális strómasejtek: Memória CD4+ sejtek és plazmasejtek életbentartása

19 CD27: a memória B sejtek markere
TNFR család I típusú glykoprotein, CD27+ sejtek száma korral nő, Liganduma: CD70 Plazmasejt képződéshez vezet CD27– B sejtek CD27+ B sejtek 60 % % Keskeny cytoplazma, Nagy cytoplazma Ig termelés alacsony Ig termelés: magas Szomatikus hipermutáció Nincs van

20

21 Preferential survival of antigen-specific memory CD62LhiCD8+ T cells
following influenza virus infection. TEM TCM Figure 1. Preferential survival of antigen-specific memory CD62LhiCD8+ T cells following influenza virus infection. (A) The numbers of influenza-specific CD62LhiCD8+ T cells, but not CD62LloCD8+ T cell sets, are stable following the primary infection. (B) This is in contrast to the relative frequencies of CD62Llo and CD62Lhi effector and memory T cell populations as based on our published data in

22 Early establishment of a stable TCR repertoire composition for memory TEM CD62Llo and TCM CD62Lhi sets. TEM TCM Early establishment of a stable TCR repertoire composition for memory TEM CD62Llo and TCM CD62Lhi sets. Schematic summarizing the results of TCR repertoire analysis of the TEM CD62Llo and TCM CD62Lhi subsets for influenzaspecific DbNP366 + and DbPA224 +CD8+ T cells at the acute phase of infection (d8-d15), early memory (d28) and late memory (d180-d500). Data are based on n=3018 sequences published in (25).

23 ”Csökkenő potenciál” model CD8+ T sejtek fejlődésére
Key: terminal effectors, dark pink; suboptimal memory, light pink; memory precursors, light green; effector memory, intermediate green; central memory, dark green. Figure 3. The decreasing potential model of memory CD8 T-cell development. Optimal antigenic stimulation triggers a developmental program of expansion and differentiation of naïve T cells into effectors. Following antigen clearance, a fraction (5–10%) of the cells progressively differentiate into potent long-lived memory cells in the absence of antigen [41, 47 and 86] (light blue shaded box). Whereas suboptimal stimulation might lead to limited CD8 T cell expansion and/or impaired memory development and function [49 and 87], the decreasing potential model postulates that prolonged antigenic stimulation impairs memory generation potential by driving the cells towards a terminally differentiated effector phenotype with each successive stimulus and cell division. This is accompanied by an increasing susceptibility to apoptosis, and cells receiving the highest magnitude of stimulation bear the lowest potential to survive and differentiate into memory cells. Furthermore, the generation of TEM and TCM lineages, and the time needed for differentiation into TCM cells (represented by the length of dotted line), are also regulated by the duration and/or strength of antigenic stimulation. Whereas a short duration of antigenic stimulation favors development of TCM, longer stimulation promotes the differentiation of terminal TEM cells. Apart from antigen, additional cell-extrinsic variables including the cytokine and chemokine milieu, costimulatory and inhibitory signals (dependent on the type and activation state of the APC), interaction with other cell-types (e.g. CD4 T cells), and the anatomic location might further impact the qualitative and quantitative aspects of a developing T-cell response and the ensuing memory differentiation and maintenance. Key: terminal effectors, dark pink; suboptimal memory, light pink; memory precursors, light green; effector memory, intermediate green; central memory, dark green.

24 Memória sejtek és effektor sejtek keletkezése
Nature Reviews Immunology 2, (2002); Memória sejtek és effektor sejtek keletkezése Perzisztáló antigén? FDC függő Vörös pulpa, LN:medulla Terminálisan differenciált sejtek Figure 1 | Generation of memory cells and effector cells.   a | Development of memory B cells and effector B cells (plasma cells) occurs in two phases. Short-lived plasma cells that make mostly IgM (but some IgG) are generated during the primary response and occupy sites, such as the splenic red pulp or lymph node medulla. B cells are also seeded to follicles to form germinal centres in this early phase. The second phase involves the formation of the memory B-cell pool and seeding of long-lived plasma cells to the bone marrow (making predominantly switched isotype antibodies). Plasma cells are terminally differentiated and do not give rise to memory cells. All arrows are driven by antigen and T-cell help. b | Development of memory T cells (CD4 and CD8). After activation, cells differentiate into effector T cells. Memory T cells might be generated by divergence from this pathway or directly from effector T cells. There might be two subsets of memory cells: quiescent, central memory cells that recirculate from blood to secondary lymphoid organs, and effector memory cells that migrate through tissues and deliver a very rapid response on reactivation with antigen. Effektor memória T sejtek migrálnak a szövetek között , nagyon gyors választ adnak az ujabb antigén ingerre Centrális memória T sejtek: recirkulálnak a vérből a másodlagos nyirokszervekbe

25 A Centrális memória T sejtek (CD62Lhi, CCR7+) a másodlagos nyirokszervekben lokalizálódnak,
Citotoxikus aktivitásuk alacsony, és korlátozott migrációs képességgel rendelkeznek. Erős proliferáció a másodlagos stimulusra Az Effektor memória T sejtek (CD62Llow, CCR7–) a nem limfoid szövetekbe (pl. nyálkahártya) kerülnek a periférián, citolitikus képességűek, és a vérkeringéssel cirkulálnak, lépbe jutnak (nyirokcs-ban nincs). IFNg termelés, kevés proliferáció jellemző. Gyors kezdeti válasz. Both molecules interact with components displayed on the high endothelial venules of lymph nodes - CD62L interacting with carbohydrate moieties termed lymph node addressins while CCR7 binds the ”homeostatic‘ chemokines CCL19 and CCL21. Memory cells that express these two molecules are termed central memory (TCM), and efficiently traffic into lymph nodes, but are not predominant in peripheral tissues. In contrast, effector memory (TEM) cells do not express CCR7 or CD62L and are excluded from lymph nodes, but can be found in the spleen (especially in the red pulp (Jung et al., 2010)) and are prevalent in non-lymphoid tissues (Masopust et al., 2001). In addition to these trafficking differences, the TCM pool exhibits improved long-term survival and enhanced proliferation upon antigen restimulation, compared to the TEM population, while the TEM subset, especially cells isolated from tissues, show more rapid deployment of effector functions compared to TCM (Kaech and Wherry, 2007;Jameson and Masopust, 2009). Rövid ag stimulus Tcm-nek kedvez, hosszabb stimulus Tem-nek kedvez. További jelek , amelyek döntőek: citokin, kemokin háttér, costimulátor és inhibitor szignálok, más sejtekkel való kh (CD4+) , anatómiai lokalizáció befolyásolja a Tcm, Tem kialakulását

26 Rezidens memória T sejtek: nem recirkuláló, Tem-hez hasonló CD8+ sejtek, bőr, tüdő, agy, nyálmirigy – határfelületeken: első védelmi vonal, a periférián történő infekció kivédésében szerepelnek. Melyik CD8 memória sejt csoport biztosítja az optimális védelmet a patogénekkel szemben? A memória T sejtek eloszlása és reaktiválása szizstémás és lokális infekciót követően: Pl. bakteriális szepszis Pl. virus fertőzés bőr Figure 1. Schematic of memory T cell distribution and reactivation during systemic and local infection. The model depicts the response to infection of animals with pre-existing memory CD8 T cell populations. Different populations of memory cells occupy distinct niches: TCM are restricted to lymphoid tissues, recirculating TEM and long-lived effector-like cells traffic through tissues and certain lymphoid sites (such as the splenic red pulp – red triangles) while TRM are strictly limited to tissue parenchyma. Upon infection via the blood (such as bacterial sepsis), pathogens may initially be controlled by effector-like and TEM populations at entry sites (e.g. the splenic red pulp and marginal zone). Subsequently, activation and clonal expansion of TCM increases the frequency of secondary effector cells. In this scenario, TRM are not engaged in the response. However, during a peripheral infection (for example, viral infection in the skin), initial pathogen control is mediated by the TRM pool. This inflammatory response may recruit circulating TEM (and, potentially TCM) to the site of infection. Subsequent responses initiated in draining lymphoid tissues would control systemic spread. Vörös pulpa

27 T sejt 2-3 hónap az optimális a primer és ráerősítő oltás között Figure 1. Using the Principles of Memory T Cell Differentiation to Determine the Optimal Time for Boosting (A) After primary vaccination, naive T cells proliferate and differentiate into effector cells. The majority of these effectors undergo apoptosis but a subset further differentiates to form the pool of long-lived memory cells. This model of progressive memory T cell differentiation is characterized by a gradual acquisition of memory T cell properties such as the ability to make effective proliferative responses upon re-encounter with antigen. (B) Based on this memory differentiation program, the optimal time for boosting is during the late stages of the effector to memory transition, and therefore an interval of 2–3 months is recommended between the prime and the boost. Immunity 33, 2010

28 reduced proliferative potential.
Repeated Immunizations Drive Memory T Cells toward Terminal Differentiation: Implications for Memory Cell Heterogeneity and Protective Immunity (A) Repetitive antigen encounter results in memory T cells with more effectorlike properties and with preferential location in nonlymphoid tissues but with reduced proliferative potential. (B) If all memory Tcells are recruited into the response after each booster shot, then the entire pool of memory T cells would be driven toward terminal differentiation (C) If only some of the memory T cells are activated upon subsequent booster immunizations, then one would end up with a heterogenous pool of memory T cells with both effector-like cells at mucosal sites and also memory cells with proliferative capacity. Immunity 33, 2010

29 Using Drugs to Modulate Memory CD8+ T Cell Differentiation
(A) Antigen-specific CD8+ T cell responses after an acute infection or vaccination. During the expansion phase, naive CD8+ T cells proliferate and then become effector cells. After clearance of the pathogen, 90% to 95% of the effector T cells die during a contraction phase. The surviving 5%–10% of the antigen-specific T cells become the memory population. (B) Without rapamycin treatment. (C) Rapamycin improves both quality and quantity of memory CD8+ T cells. Rapamycin treatment increases memory precursor effector cells that survive during the contraction phase and also improves quality of memory T cells by accelerating effector to memory T cell formation. Immunity 33, 2010

30 T-sejtek stimulálása: tolerancia, memória és krónikus válasz kiváltása
Figure 2. T-cell priming for tolerance, memory and chronic responses. (a) Weak antigenic stimulation. T cells proliferate and become hypersensitive to antigen, but remain unfit and die if stimulation is not sustained. Antigen presented by rare immature DCs, low-avidity TCRs and extreme competition will favor this outcome. (b) Strong antigenic stimulation; antigen is cleared. T cells proliferate and reach various stages of differentiation, depending on the cumulative strength of TCR and cytokine stimulation received during interactions with mature DCs. Most cells reach the stage of tissue homing effectors, whereas some cells reach intermediate stages. Upon antigen clearance, survival of the expanded T cells depends on the resources available in the niche they occupy and on their intrinsic capacity to compete for those resources, primarily IL-7 and IL-15. The less differentiated cells are rescued as TCM, whereas the most differentiated cells are rescued as TEM. Although TCM can mediate secondary responses, the relatively low number of TEM remaining might not be sufficient to mediate immediate protection in some cases. (c) Strong antigenic stimulation; antigen is not cleared. Persisting antigen drives continuous proliferation and terminal differentiation of all T cells. High numbers of effector cells are maintained for some time and mediate effective protection from a challenge. Terminal differentiation, however, prevents the generation of TCM. The term ‘memory cells’ should be avoided in this case, as stimulation is ongoing. Upon antigen removal, effector cells disappear and memory T cells do not develop.

31 homeosztázisának változásai
A memória T sejtek homeosztázisának változásai Másodlagos válasz: magasabb szint Átmeneti emelkedés: az új memória sejtek kiszorítják a régieket, de IFN g és IL-15 szint emelkedik -> bystander hatás régi Tmem sejtekre Antigén specifikus memória pool csökkenhet a homeosztázis fenntartása érdekében Figure 5 | Alterations in memory T-cell homeostasis. Many events can alter the homeostasis of memory T cells. After a primary infection, antigen-specific T cells undergo clonal expansion and subsequent contraction. As the contraction-phase ends, some antigen-specific T cells remain as a stable population of memory T cells that persists over long periods of time. a | After a secondary infection with the original microorganism, memory T-cell populations expand rapidly to high levels, but undergo a slow contraction phase. This secondary response boosts the level of memory T cells to a higher level, resulting in a new level of homeostasis. b | During an infection with a different pathogen, the activation events induce an increase in the level of interferons, and thereby interleukin-15 (IL-15), which could then act on the IL-15-sensitive pre-existing memory CD8+ T-cell population. IL-15 acts in a bystander manner to increase memory CD8+ T-cell proliferation temporarily. c | Attrition of antigen-specific memory T cells can also occur after infection with a heterologous virus. As the size of the memory T-cell pool is constrained, a decrease in the number of memory T cells specific for other antigens might take place to maintain homeostasis.

32 A memória-készlet homeosztázisának modellje
Figure 2 | Model of homeostasis in the memory pool.   a | For each new memory cell that is generated, one must be deleted. This should be on the basis of their ability to access or respond to survival factors, such as antigen or cytokines, both of which replenish the memory pool and can balance homeostatic deletion. b | A simple model of how this might work is suggested: the expression of receptors for the survival factor (for example, IL-15 receptor; IL-15R) decays over time after antigen stimulation. So, the longer the time from encounter with antigen, the more likely the cells will be lost from the system. Túlélést biztosító receptor expressziója csökken

33 A T sejtek differenciálódásának ellenőrzési pontjait szabályozó citokinek
Figure 1 | Cytokines control T-cell differentiation checkpoints. Cytokines can affect T-cell proliferation and survival at many stages of the immune response. During initiation of the T-cell response, interleukin-15 (IL-15) might be involved in dendritic-cell (DC) activation. After T-cell receptor (TCR) ligation of peptide–MHC, substantial T-cell clonal expansion occurs and might be driven, in part, by IL-2. IL-15 might also enhance the proliferation of antigen-specific T cells. IL-2 can also control the late clonal-expansion phase by inducing T-cell death. The massive cell death that occurs during the contraction phase results in the loss of most antigenspecific T cells. Both IL-15 and IL-7 might rescue T cells from cell death at this stage, thereby allowing memory T-cell generation. Memory T cells are maintained long term by undergoing a low level of proliferation, which depends on IL-15. IL-7 seems to be more important for promoting the survival, rather than the growth, of memory T cells. IL-7 és IL-15 is megmentheti a T -sejteket a haláltól  kedvez a memória T-sejtek kifejlődésének. Memória T sejtek: IL-15 -függő proliferáció, IL-7: memória T-sejtek túlélését segíti

34 A citokin receptor alegységek eltérő kifejeződése az immunválasz során
Konstitutív expresszió IL-7Ra Relative expression level IL-15Ra IL-2/IL-15Rb The interleukin-7 receptor α-chain (IL-7Rα) and IL-15Rα are constitutively expressed by naive T cells. Expression of IL-15Rα has been determined using a chimeric IL-15–Fc molecule to detect IL-15 binding, as no IL-15Rα-specific antibodies are available at present. Although the binding of IL-15–Fc depends on the expression of IL-15Rα, it is possible that other cytokine-receptor subunits contribute to IL-15–Fc binding. Although naive T cells do not express IL-2Rα, expression of IL-2Rα is rapidly upregulated by T-cell activation, but usually declines before the proliferative peak of the response. The levels of expression of IL-15Rα and IL-2/IL-15Rβ are increased after activation, and high levels of expression are retained throughout the memory-cell stage. Expression of IL-7Rα is downregulated by T-cell activation, which might promote cell death. Conversely, expression of IL-7Rα increases as the immune response proceeds, reaching high levels on memory CD8+ T cells. The common cytokinereceptor γ-chain (γc) is not differentially expressed between naive and memory-phenotype T cells (not shown IL-2Ra response Naiv Activated T cells Memory T cells

35 Az IL-15 közvetett és közvetlen hatása a memória sejtek fenntartására
In vivo az IL-15 elsősegítheti pozitív regulátor termelését, vagy elnyomhatja negatív regulátor termelését IL-15R bemutathatja IL-15-t másik sejtnek, mely IL-15  negatív, de IL-15β pozitív Direct and indirect effects of IL-15 on memory T-cell maintenance. a | There is substantial in vitro evidence that interleukin-15 (IL-15) can act directly on T cells. However, in vivo, the effects of IL-15 might not be mediated through IL-15 receptor (IL-15R) expressed by T cells. b | There are many other cell targets for IL-15, which indicates that IL-15 might act indirectly to confer a positive effect on memory T-cell turnover. In an autocrine or paracrine manner, IL-15 might act to increase expression of a factor that directly potentiates memory T-cell proliferation. Alternatively, factors might exist that negatively influence memory CD8+ T-cell division. If so, then IL-15 might inhibit a negative regulator of memory CD8+ T-cell division. c | A new scenario has been proposed in which IL-15Rα presents IL-15 to neighbouring cells expressing only the IL-2/IL-15Rβ and common cytokine-receptor γ-chain (γc) subunits108. In this situation, a cell does not require expression of IL-15Rα to be responsive to IL-15.

36 Naív sejtek száma csökken, memória sejtek száma nő
Memória, autoimmunitás és öregedés B és T sejtek reagáló képessége az antigénekre a korral csökken, de az autoreaktív ellenanyagok mennyisége magasabb, a B sejt repertoár nem változik Naív sejtek száma csökken, memória sejtek száma nő

37 Az immunológiai memória és a protektív immunitás közötti összefüggés himlő oltást követően
Relationship between immunological memory and protective immunity following smallpox vaccination. Two independent studies [20,24] have quantitated the duration of T-cell- and B-cell/antibody-mediated immunity over the course of several decades and came to remarkably similar conclusions: T-cell memory declines slowly over time, with a half-life of 8–15 years (representative thin line), whereas serum antibody responses (and B-cell memory; [20]) are maintained essentially for life with little or no observable decline (representative bold line). Immunological memory quantitated directly ex vivo does not necessarily demonstrate protective immunity; this can only be accomplished by natural exposure or experimental challenge experiments with the virulent pathogen of interest. In this regard, the protection afforded by smallpox vaccination was determined at the indicated intervals (bar graph inset) following immunization and shows that >90% of vaccinees are protected against lethal smallpox (normally 30% mortality in unvaccinated individuals) for at least 60 years post-vaccination [47,48]. Similar results showing long-term immunity were observed during imported smallpox outbreaks throughout Europe between 1950 and 1971 [49,50], decades after endemic smallpox had been eradicated [49].