APC abd Ag presentaion APC abd Ag presentaion

APC abd Ag presentaion

1. APC Ag presentation

2. APC An (antigen-presenting cell ) is a cell that displays antigen in association with major histocompatibility complex (MHC) at its surface. ( effector cells) T -cell has specific receptors (TCR) peptide–MHC complexes ……communicate information to one of the the immune system,  T cells ,,,,,,,, which recognize these complexes using their T-cell receptors (TCR) dendritic cells (DCs ) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses.

3. APCs includes any cell that retains the capacity to express antigen on its cell surface in association with only an MHC I protein complex . This includes all nucleated cell types, Two fundamental categories of antigen-presenting cells exist: professional and nonprofessional. Professional APC.. dendritic cells, B cells,  monocytes , macrophages, and  neutrophils  are bone marrow–derived leukocytes that comprise the professional antigen-presenting cells of an individual. 

4. APCS for class II CD4 1-dentritic cells- -- the only initate T cell responsein the Tcell naiive 2- mononucular macrophage- - in effector phase of CD4 3-B lymphocyte-  during humoral response 4- Vascular endothelial cells A ll 3 are professional but dentritic the only the sole function to capture and presentation

5. P roperties of APS ( AbulAbbas ) C ell type c lass MHC II costimulators P rinciple function dentritic INF gamma w maturation INF gamma CD40-CD40L I nitiation of T cell response macrophage LPS LPS –INF gamma CD40-CD4-L C d(80-86(B 7) with CD 28 interaction E ffector phase of T cell mediated immune response B lymphocyte IL 2, 4 ,5 CD40-CD4-L interaction Ag receptor cross link Ag presentation to CD 4 helper T cell in humoral immune response (B and T cell interaction) Vascular enothelium INF gammalp S pecific T cell at site of Ag deposition

6. R equirment for Ag presentatioin 1- endocytosis and proteolytic digest protein 2- express C lass II or class I for Ag presentation 3- secrete co stimulatory molecules? Dentritic cells were first discovered in 1973 by Ralph Steinman, who was awarded a Nobel Prize in 2011 for that discovery. 

7. S ignals during Ag presentation 1- signal one :MHC II antigen complex 2- co stimulatory molecules ( B7-1  and  B7-2 , also called  CD80  and  CD86 ) are induced on APCs and allow activation of CD28 on the T cells. ICoS- OX 40 ne does not want continuous  T-cell activation , there is also another set of co-receptors which inhibit T-cell activation. They are called  co-inhibitory receptors ,   and include  CTLA-4 and PD-1 . These molecules are only expressed on T cells that have already been activated. Stimulation of these induced co-inhibitory receptors will curtail T-cell activation, and therefore contribute to a balanced immune response. Indeed, defects in these co-inhibitory receptors lead to aberrant immune responses, such as lymphoproliferation and autoimmunity he specific B-cell receptor ( BCR , an immunoglubulin molecule attached to the membrane of the B cell) recognises the antigen in native form, as opposed to the TCR that recognises antigenic peptides. Costimulation of B cells is notably achieved by the molecule CD40 . CD40 ligand is expressed on T cell 3- signal 3 cytokine release

8. plasmacytoid dendritic cells constitute 0.1–0.5% of human peripheral blood mononuclear cells (PBMCs).   3 ,  4   Freshly purified pDCs manifest a plasmacytoid morphology, with rough endoplasmic reticulum and Golgi apparatus. Upon activation, pDCs gain dendritic cell‐like morphology and produce massive amounts of type I interferons (IFN‐I), for example most of the IFN‐I detectable in the blood following viral infection in mice and humans.   1   ,  2   The IFN‐I secretion by pDCs is mainly mediated through the activation of the endosomal Toll‐like receptors (TLRs) TLR7 and TLR9, with cytosolic receptor initiating pathways playing an important supplementary role.   5   Apart from IFN‐I, pDCs could also secrete pro‐inflammatory cytokines and chemokines and express co‐stimulatory or co‐inhibitory molecules which facilitate pDCs to cross‐prime CD8 +  T cells and present antigens to CD4 +  T cells.   2   ,  6

9. lasmacytoid dendritic cells were initially identified as a unique cell subset that respond to viruses with rapid and massive production of IFN‐I, and play a central role in the antiviral immune response.   2 Moreover, pDCs could also respond to certain non‐viral pathogens such as bacteria (e.g. Chlamydia pneumoniae)   51   and apicomplexan parasites (e.g. Plasmodium).   52   ,  53   The recent advances in pDCs in anti‐infectious immunity are not within the scope of this review, but have been very well summarised by Reizis. 54   Recognition of either pathogen‐derived nucleic acids or synthetic TLR ligands such as CpG ODNs initiates IFN‐I secretion by pDCs , which is mainly (albeit not exclusively) mediated through the activation of the endosomal TLR7 and TLR9, and the subsequent myeloid differentiation primary response protein 88 (MYD88)–interferon regulatory factor 7 (IRF7) pathway.   55   In addition, the MYD88–NF‐ κ B pathway is also activated, leading to the secretion of pro‐inflammatory cytokines and chemokines, and the expression of co‐stimulatory molecules. TLR7 senses RNA viruses and endogenous RNA, whereas TLR9 detects prokaryotes containing unmethylated CpG‐rich DNA sequences and endogenous DNA. Both TLR7 and TLR9 sense synthetic CpG ODNs, and different classes of CpG ODNs have been developed to perform different immune functions. CpG‐A is a strong inducer of type I IFNs, whereas CpG‐B is a potent stimulator of maturation and the production of cytokines and chemok

10. S ignal one (Ag presentation) once T cells leave the thymus, they circulate throughout the body until they recognise their antigen on the surface of  antigen presenting cells  ( APCs ). The  T cell receptor (TCR)  on both  CD4 +  helper T cells  and  CD8 +  cytotoxic T cells  binds to the antigen as it is held in a structure called the MHC complex, on the surface of the APC. This triggers initial activation of the T cells. The CD4 and CD8 molecules then bind to the MHC molecule too, stabilising the whole structure. This initial binding between a T cell specific for one antigen and the antigen-MHC it matches sets the whole response in motion. This normally takes place in the secondary lymphoid organs.

11. Signal Two(co stimulatory molecules ) In addition to  TCR  binding to antigen-loaded MHC, both  helper T cells  and  cytotoxic T cells  require a number of secondary signals to become activated and respond to the threat. In the case of helper T cells, the first of these is provided by  CD28 . This molecule on the T cell binds to one of two molecules on the APC –  B7.1 (CD80)  or  B7.2 (CD86)  – and initiates T-cell proliferation. This process leads to the production of many millions of T cells that recognise the antigen. In order to control the response, stimulation of CD28 by B7 induces the production of  CTLA-4 (CD152) . This molecule competes with CD28 for B7 and so reduces activation signals to the T cell and winds down the immune response. Cytotoxic T cells are less reliant on CD28 for activation but do require signals from other co-stimulatory molecules such as  CD70  and 4-1BB ( CD137 ).

12. T cells must recognise foreign antigen strongly and specifically to mount an effective immune response and those that do are given survival signals by several molecules, including  ICOS ,  4-1BB  and  OX40 . Unlike TCR. - not continuous present it ensures T cells are only activated by APCs which have encountered a pathogen and responded No co-stimulation- --  switches the T cells off,  CD28 is a- -----.> powerful early stimulator, whereas 4-1BB ---  is more critical in the later activation of cellular expansion phases, particularly memory T-cells Front Oncol.  2023; 13: 1200914.  Published online 2023 Aug 18.  doi :  10.3389/fonc.2023.1200914 ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype Eider Moreno-Cortes ,  1 , 2  Pedro Franco-Fuquen ,

13. OX40 signaling enhanced CAR-T cells’ (chimeric antigen receptors )cytotoxicity and reduced exhaustion markers, thereby maintaining their function in immunosuppressive tumor microenvironments. Therefore, in this study, we evaluated the combination ICOS-OX40 as a novel 3G approach compared to the previously published combination C

14. S ignal Three (cytokines) Once the T cell has received a specific antigen signal and a general signal two, it receives more instructions in the form of cytokines. These determine which type of responder the cell will become – in the case of helper T cells, it will push them into  Th1 type  (cells exposed to the cytokine IL-12),  Th2  (IL-4), or  IL-17  (IL-6, IL-23). Each one of these cells performs a specific task in the tissue and in developing further immune responses. The resulting cell population moves out to the site of the infection or inflammation in order to deal with the pathogen. Other cells present at the tissue site of inflammation– such as neutrophils, mast cells, and epithelial cells – can also release cytokines, chemokines, and other molecules which induce further activation and proliferation of the T cells.

15. P rofessional APC . and Liu, 2002 ).

16. Maturation of dentritic cell

17. T ypes of conventional dentritic L ymphoid resident migratory Tissue-derived dendritic cell Lymphoid-resident dendritic cells are located in an immature state within either the spleen or lymph nodes. O nce capture antigen I t mature and distingused by their surface receptors . Tissue-derived dendritic cells remain in peripheral tissues(lung- Payer patch where they capture antigens--  migration to the local lymph nodes to interact with--  lymphocytes In the spleen --  the task of screening the blood for pathogens. In the lymph nodes, --  they capture antigens from migratory dendritic cells emigrating from peripheral tissues or from material draining directly through the lymphatic conduits. in the spleen and LNs can very efficiently activate antigen-specific T cells  in vivo  ( 37 T issue dentritic cells (portal of bacteria) 1- interstitial lung 2-payer patches 3-kappfer cells 4-langerhans epdermis

18. Recruitment of specific DC and/or monocytes in inflamed tissues may play a key role in the pathophysiology of the disease promoting T helper cell (Th) polarization depending on the environment. In JIA (the most common inflammatory arthropathy in children), severe chronic inflammation in the synovium leads to joint destruction and additional extra-articular manifestations (such as uveitis), 

19. pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) . These patterns are found in molecular components of bacterial cell walls, DNA, lipoproteins, carbohydrates, and other structures bind to pattern-recognition receptors or PRRs associated with body cells to induce  innate immunity This receptor is expressed in various lymphoid tissues and activates B and T lymphocytes. It has been shown to control the migration of memory T cells to inflamed tissues, as well as stimulate dendritic cell maturation. The chemokine , CCR7 +  T cells continued to migrate into afferent lymph.

20. unique T-cell differentiation by conventional dentritic cell conventional dendritic cell pool preferentially drive unique T-cell differentiation. For example, distinct subsets are better at evoking either CD4 +  or CD8 +  T-cell responses while others only drive clonal expansion of memory T-cell populations ( Heath and Carbone, 2009 ). These recent findings justify further scrutiny of the precise functions of individual conventional  dendritic cell subsets  in order to provide insight into new strategies for vaccine development that target-tailored immune responses.

21. Plasmacytoid dendritic cells Different from their other family members not only by morphology , cell surface markers, but also in function (Grouard et al., 1997). To date, the primary function of plasmacytoid dendritic cells appears to be the secretion of vast amounts of type I interferon, thus playing a key role in the limitation of viral replication and dissemination . Less effective in lymphocyte activation. However, they present antigens much less effectively than other dendritic cells due to reduced antigen uptake and inefficient processing, and loading of antigens onto MHC molecules. ).

22. Plasmacytoid dendritic cells between tolerance and immunity Recent studies identified regulatory markers in pDCs such as programmed death-ligand 1 (PD-L1), Indoleamine 2,3-dioxygenase (IDO) and granzyme B ( GrB ) which might mediate a shift from Th2 T cell response towards regulatory T cells, t hus promoting tolerance. The role of plasmacytoid dendritic cells in inducing tolerance during allergen specific immunotherapy. Schmitt, Anna 2024 DCs are considered the most efficient APCs capable of efficiently processing and presenting exogenous antigens on both MHCII and MHC I molecules to naïve CD4 +  and CD8 +  T cells, respectively, thus initiating the adaptive immune response.

23. T ypes of costimulatory molecules

24. 3rd signal cytokine production(Il12)

25. iDCs in the resting state are considered to be immature but primed to acquire pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)  in situ  through a variety of surface and intracellular receptors, namely ( 1 ) cell surface C-type lectins, ( 2 ) surface and intracellular TLRs, and ( 3 ) intracellular helicases that recognize nucleic acids, such as retinoic acid-inducible gene I (RIGI) ( 18 ) ( Table 1 ).

26. DCs undergo a series of phenotypic and functional changes upon exposure to activation signals, leading to their maturation ( 10 ). This process is associated with the following events: (1) downregulated antigen-capture activity, (2) increased expression of surface MHC class II molecules and enhanced antigen processing and presentation, (3) increased levels of chemokine receptors, e.g., CCR7, which allows migration of the DC to lymphoid tissues; (4) increased expression of costimulatory molecules associated with the capacity to stimulate or suppress T cells through different signaling axes: CD80/CD86-CD28, CD40-CD40L, OX40L-OX40, ICOSL-ICOS and galectin (GAL)9-TIM3, CD80-CTLA4, PDL1-PD1, PDL2-PD1, respectively ( Figure 2 ); and (5) enhanced secretion of cytokines and chemokines, leading to the development of an immune response T cell subtypes, e.g., CD4 +  T cells such as T H 1, T H 2 and Tregs 0.  Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity.  Front Immunol . (2013) 4:438. 10.3389/fimmu.2013.00438 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

27. M ature DC Mature DC exhibit the characteristics of high expression of the surface MHC-II and costimulatory molecules (CD80/CD86 and CD40). On the contrary, Tol-DC are often characterized by low expression of MHC-II and CD80/CD86 and CD40, termed as a state of “semi-maturity” ( 8 ). Additionally, Tol-DC are also featured with increased expression of anti-inflammatory molecules, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF- β), and decreased levels of IL-12p70 and other proinflammatory cytokines ( 22 ).

28. PAD 1 and PAD L Vitamin D3 (VitD3) is a fat-soluble hormone that can be acquired from food or be biosynthesized in the skin upon ultraviolet-B radiation and is commonly applied as a drug for rickets, which is considered to be one of the most commonly used strategies for inducing Tol-DC  in vitro . VitD3-Tol-DC show low expression of MHC-II, CD80, CD86, and CD40 and high secretion or expression of IL-10, in PD-1 is an important inhibitory molecule expressed on T cells, and PD-L1 is its ligand expressed on DC. The interaction between PD-1 and PD-L1 delivers inhibitory signals to T cells and contributes to the anergy of T cells ( 90 ). no Y, Perez-Gutierrez A, Nakao T, Dai H, Camirand G, Yoshida O, et al.  Graft-infiltrating PD-L1(hi) cross-dressed dendritic cells regulate antidonor T cell responses in mouse liver transplant tolerance .  Hepatol (Balt Md)  (2018)  67 ( 4 ):1499–515

29.  Although other cells such as macrophages and B cells are also able to present antigens  via  MHC, DCs are the only cell type to activate naïve T cells and to induce antigen-specific immune responses in all adaptive immune cells ( 4 ). They can for instance directly induce antibody production by presenting intact antigen to antigen-specific B cells without engaging T cells ( 5 ). DCs take a guiding role in immune responses as they interrogate, interpret, and transmit the nature of the antigenic stimulus, thereby shaping even T cell polarization  via  different intracellular signaling pathways ( 6 ). . Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.  Annu Rev Immunol  (2013) 31:563–604. doi:10.1146/annurev-immunol-020711-074950

30. human tolerogenic DCs are induced by various immunosuppressive drugs (Figure  3 ) that are often systemically used to control excessive immune responses like corticosteroids, rapamycin, cyclosporine, or by acetylsalicylic acid ( 58 ). For instance, the corticosteroid dexamethasone is capable of inducing tolerogenic DCs that exhibit low expression of co-stimulatory molecules combined with highly expressed inhibitory receptors ILT-2 and ILT-3 and secrete large amounts of IL-10 and IDO resulting in the induction of T cells with regulatory capacities ( 15 ,  59 – 61 ).

31.  incubation with the immunosuppressive cytokines TGF- β and IL-10 alone or in combination facilitated the generation of a tolerogenic DC phenotype (Figures  2 – 4 ) ( 48 ,  66 ). For instance, TGF- β dampens the antigen-presenting capabilities of DCs by downregulation of MHC and co-stimulatory molecules and upregulation of PDL-1 resulting in T cell anergy

32. T cell T cells cannot recognize and therefore cannot respond appropriately to ‘free’ antigens. 

33. conclusion (signal 1).  a naive  T cell  must first recognize a specific peptide–MHC complex (signal 2). Professional antigen-presenting cells express costimulatory molecules, such as B7.1 and B7.2, whose recognition by the CD28 coreceptor is essential for a T lymphocyte to be activated signal 3) :are needed and many of these are provided by the professional antigen-presenting cells, such as the proinflammatory cytokines IL-12 and type I interferon.

34. f a naive T cell engages antigen in the absence of costimulatory molecules, such as on a nonprofessional antigen-presenting cell, inactivation occurs by either ‘clonal deletion’ or an inactive state known as ‘anergy.’ Thus, these two signals are a necessity for the activation of naive T cells, but alone are insufficient to support strong T-cell clonal expansion, development of effector function, or establishment of a responsive memory pool. Instead, additional signals (signal 3) are needed and many of these are provided by the professional antigen-presenting cells, such as the proinflammatory cytokines IL-12 and type I interferon.

35. O veractivity in apoptosis

36. I mmune check points ihibitors

37. A g Ab presentation stages function :allows T cells to “see” what proteins are present in the body and to form an adaptive immune response against them Antigen presentation is the initial stage of the immune response and in which antigen-presenting cells (e.g., dendritic cells (DCs), macrophages) take up and process them into antigenic peptides so that they can be recognized by immunocompetent cells.   Result : activation or tolerization of lymphocytes,

38. he adaptive immune system views the world of antigens through the lens of MHC molecules

39. Antigens must be presented to the adaptive immune system so that specialized  antigen presenting cells (APCs)  can activate the immune system killer T-cells  can monitor the intracellular contents of all cells helper T-cells  can be alerted to both intracellular and extracellular antigens Two types of antigens are processed by cells for presentation on the cell surface endogenous antigens are proteins produced by the cell (apoptotic bodies) exogenous antigens are proteins that are taken up by the cell Both types are linked to  major histocompatability complexes (MHC)  during processing so that they can be stably exported to the cell surface they can be recognized specifically by T-cells Antigens are presented to two distinct cell populations including CD4+ helper T-cells that recognize antigens loaded onto MHC class II CD8+ killer T-cells that recognize antigens loaded onto MHC class I

40. Antigen Processing Pathways Feature MHC Class I MHC Class II Function Allow for sampling of intracellular antigens Signal that a cell is infected or abnormal Allow for sampling of extracellular antigens Signal that pathogens are within the host Target cell CD8+ killer T-cells Rule of 8: (MHC) 1 x (CD) 8 = 8 CD4+ helper T-cells  Rule of 8: (MHC) 2 x (CD) 4 = 8 Antigens Endogenous antigens Exogenous antigens Degradation By proteosomes in the cytosol By proteases in the phagosome Translocation Into ER by TAP proteins Into endosomes after phagocytosis Loading Directly bind to MHC I Bind to MHC II after release of invariant chain Defect Absent CD8+ activity Absent CD4+ activity

41. Cytotoxic T lymphocytes (CTLs) often called CD8 +  T cells, are a adaptive immune system and play an important role in immune defense against intracellular pathogens such as viruses and bacteria and against tumors  the function of the class I MHC is  to display intracellular proteins to cytotoxic T cells (CTLs) . PAD1 PAD L1 binding induce T cell anergy, be blind, blockits respon s e to MHC1

42. Step 1: acquisition of antigens Receptors with various degrees of specificity participate 46 , 50 . include the B cell receptor (BCR) for an antigen, the mannose receptor, complement receptors, Fc receptors and probably scavenger receptors, all of which deliver the captured antigen to the various compartments of the endocytic pathway 5 Cells engaged in MHC-II-restricted presentation acquire antigen?s  

43. MHC-I molecules sample Autophagy targets damaged cytoplasmic organelles such as mitochondria and cytoplasmic viral replication machineries to a lysosomal compartment for degradation 55 . by Macropinocytosis .. MHC-I molecules sample the proteome of MHC-I-positive cells. Cytosolic proteins are also continuously turning over,, and this involves proteolysis, by the–proteasome system 61 . All nucleated cells express MHC-I . viral protein synthesis contributes to the proteome of the infected cel l and serves as a source of antigens for MHC-I molecules 63 Proteins in the extracellular space can also contribute to peptides presented by MHC-I molecules. This is referred to as ‘cross-presentation’ Membrane and secreted proteins that fail to pass quality control in the ER are expelled into the cytosol in a process referred to as ‘dislocation’ or ‘ER-associated degradation’ 65 . These discarded proteins likewise contribute to the pool of antigens sampled by MHC-I molecules.

44.       View all journals nature    nature reviews immunology    review articles    article Review Article Published: 13 April 2022 A guide to antigen processing and presentation Novalia Pishesha ,  Thibault J. Harmand  &  Hidde L. Ploegh   Nature Reviews Immunology   volume 22 , pages 751–764 (2022) Cite t

45. Step 2: tagging antigens for proteolysis into peptides

46. S tages of T cell cytotoxicity  pro-apoptotic molecules through the release of cytotoxic granules.  CD8 +  T cells can induce apoptosis by ligation of the receptor Fas and the Fas ligand ( Fas L), which are expressed on lymphocytes and infected target cells. Activated CD8 +  T cells also produce several cytokines that contribute to host defense, including IFN γ, TNF α, and lymphotox

47. It normally acts as a type of “off switch

48. PD-1 is a checkpoint protein on T cells . PDL on cancer cell PD-1 inhibitors Examples of drugs that target PD-1 include: Pembrolizumab (Keytruda) Nivolumab ( Opdivo ) Cemiplimab ( Libtayo ) PD-L1 inhibitors Examples of drugs that target PD-L1 include: Atezolizumab ( Tecentriq ) Avelumab (Bavencio) Durvalumab (Imfinzi)

49. P rogrammed cell death (apotosis) Chronic antigen-specific stimulation of CD8 T cells can cause functional exhaustion during persistent infections and cancer ( McLane et al., 2019 ). Programmed cell death protein 1 (PD-1) is an immune checkpoint that acts as a nonredundant negative regulator of T cell function and can be effectively targeted by immunotherapy 

50. programmed programed refers to those physiological kinds of cell death that occur during the developmental phase of the embryo and tissue homeostasis ( 1 ). Apoptosis is a type of programed cell death occurring during development and aging and helps to maintain tissue homeostasis. The term apoptosis was first coined by Kerr et al. to describe cell death with specific morphological features, including cell shrinkage (pyknosis), cytoskeleton remodeling, chromatin condensation, nuclear fragmentation ( karyorrhex

51. NETosis is a special form of death executed by neutrophils, in which nuclear chromatin, histones, and granular antimicrobial proteins are extruded from the cell forming neutrophil extracellular traps (NETs). NETs are thought to play a role in trapping pathogens, such as bacteria, fungi, viruses, and parasites, preventing dissemination and killing microbes by the inactivation of virulence factors. NETosis is physiological cell death induced by stimuli, such as pathogens and re