1) Antigen presenting cells (APCs) such as dendritic cells, macrophages, and B cells present antigen peptides on their surfaces to activate T cells. 2) APCs capture antigens through phagocytosis, pinocytosis, or receptor-mediated endocytosis and process the antigens into peptides. 3) The peptides are then presented on either MHC class I or MHC class II molecules for recognition by CD8+ or CD4+ T cells respectively, initiating an adaptive immune response.

1. Antigen presenting cells
1
Presented by
Dr. Sreelakshmi. P
1ST YEAR MDS
JKKNDCH

2. Content
• Introduction
• Antigen presenting cells
• Various Terminologies
• Requirement for Antigen presenting cells
• Mechanism of action
• Types of APC
• Properties and functions of APC
• Routes of antigen entry
• Antigen recognition by T and B cell
• Roles of APC
• Antigen processing and presentation
• Role of APC in periodontal disease
• Conclusion
• References
2

3. Introduction
• A majority of the periodontal diseases are an immunoinflammatory response elicited by the microorganisms
present in the microbial plaque.
• The immune system of the body consists of organized network of different cells and molecules that work
together in a systematic and orchestrated manner.
• The immune system defends the body against the invading microorganisms through innate (natural) and
adaptive (acquired) mechanisms.
• The stable response is mediated by T helper cells 1 (Th1) and dominated by the presence of T cells, while the
progressive lesion shows predominance of B cells through the T helper 2 (Th2) response.
- Ohlrich EJ , 2009
3

4. Antigen presenting cells
• The killing of microorganisms or neutralization of the toxins by T cells and B cells does not occur by direct
stimulation of these cells by viral or bacterial antigens.
• This lymphocyte stimulation is achieved via antigens displayed on the surface of specialized cells that are
called antigen-presenting cells (APC).
• APC :- A group of cells play important roles in the immune response which can uptake, process antigens and
present peptide-MHC complexes to T cells.
• Once initial lymphocyte response is generated following the initial processes of antigen presentation, a wide
spectrum of cell types will present antigen to the activated cells. Azuma M.2006
4

5. • The immune system primarily contains three types of APCs
namely,
1.Dendritic cells (DC) ,
2.Macrophages and
3.B-lymphocytes.
• These cells are specialized to initiate or promote the development
of lymphocyte activation and are also termed as “Professional
APC.”
• They express major histocompatibility complex (MHC) molecules
along with other mechanisms for effective antigens uptake and
expression of costimulatory molecules that promote cellular
interaction. - Cutler CW 2007
5

6. Various Terminologies
• Endogenous Ags: antigens synthesized within cells, including self and unself protein----class Ⅰ MHC
molecules.
• Exogenous Ags: antigens comes outside the cells, including self and unself protein----class Ⅱ MHC molecules.
• Antigen processing: the conversion of native proteins to peptides which can combine with MHC molecules.
• Antigen presentation: the course of formation and display of peptide-MHC complexes on the surface of APCs
and the course of peptide-MHC complexes recognition by T cells.
• Ag capturing - Endocytosis (internalization)
- Phagocytosis, Pinocytosis, Receptor-mediated endocytosis
6

7. Requirement for antigen presenting cells
T cells cannot respond to the free antigen but only to the processed antigen by the APCs
7

8. Mechanism of action of APCs
8

9. Types of Antigen presenting cells
Professional VS Non-Professional APCs
9

10. 10

11. Dendritic cell (DC)
History: DCs were first found by Steinman in 1973，named for their special spinelike projections. DCs were cultured
successfully in vitro in 1993 by Inaba.
Characteristic: The most efficient APC, can present antigens to naive T cells to elicit primary immune response.
Identification of DC :
Typical morphology - spinelike projection & stimulate naïve T cells activation
Surface markers : CD1a, CD11c, CD83(human)- high expression of classⅡMHC - co-stimulatory molecules--
CD80,CD86
Source of DC : Pluripotent hematopoietic stem cells
myeloid DC myeloid progenitor
lymphoid DC lymphoid progenitor
` GM-CSF, IL-4
11

12. Classification of DC
DC in lymphoid tissue:
Interdigitating DC (IDC)
Folicular DC (FDC)
DC in non lymphoid tissue:
Langerhans cell (LC)
DC in body fluid:
Veiled cell, Blood DC
12

13. Pre-DC
Blood
Non-lymphoid tissue
Differentiation
ImmatureDC
DistributeWidely distributed in the body
Possess ability of Ag capture and process
Cytokines and Ag
DC mature and move into lymphoid tissue
Ability of Ag capture and processing decreases
while its ability of Ag presenting increases
Development and Maturation of DC
13

14. Pre-DC stage
14

15. 15

16. Antigen Capture and Transport
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
Membrane Receptors
(C-type lectins)
Capture and Endocytose
microbes or microbial products
Process ingested proteins into
peptides capable of binding to
MHC
Microbial products recognized
by TLR
Signals and Cytokines activate
DC
(TNF)
Activated DC lose adhesiveness
and migrate to lymph nodes
16

17. Antigen Capture and Transport
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
DC
CCR7 Lymphatic Vessels
T cell zones of Lymph Nodes
CCL 19
CCL 21
Naïve
T cell
CCR7
“Colocalization”
17

18. Antigen Capture and Transport
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
DC
Capture Antigen
Present Antigen to Naïve T
cells
Activate Lymphocytes
Express high levels of MHC
Activated DC develop
Into potent APCs
18

19. Role of Dentritic cells in Antigen Capture and Display
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al. 19

20. 20

21. 2. Macrophage（ MФ）
• Stem from monocytes in blood
• Have strong phagocytosis (big phagocyte)
• Can not stimulate naïve T cells
• Capture antigens by phagocytosis, pinocytosis, receptor-mediated
endocytosis
21

22. 22

23. • B cells function as APC in the process of expansion of the immune responses through their interaction
with lymphocytes already responded to antigenic stimulus.
• Once the response is established, B cells produce specific antibodies, and effector lymphocytes including
cytotoxic T cells may be released and return to the site of infection.
• The antigen presentation to B cells is encountered in secondary lymphoid organs.
• B cells activation is initiated following engagement of the B-cell receptor (BCR) by a specific antigen.
• B cells can recognize and respond to both soluble and membrane-associated antigen, although recent
insights suggest that membrane-associated antigens are more important for B-cell activation - Carrasco
YR, 2006
3. B - Cell
23

24. 24

25. 25

26. Properties and functions of Apc
26

27. Functions of different Apc
27

28. Routes of antigen entry
28

29. Antigen recognition by T and B cells
T and B cells exhibit fundamental differences in antigen recognition.
• B cells recognize antigen free in solution (native antigen).
• T cells recognize antigen after it has been phagocytosed, degraded and small pieces of the antigen
have been bound by MHC molecules.
29

30. Role of antigen-presenting cells (Apc)
Helper T cells: recognize antigen after processing and presentation by MHC-II on APC (dendritic cells,
macrophages, B cells).
Cytotoxic T cells: recognize antigen when it is presented on MHC-I.
 Dentritic cell : Always express high levels of MHC-II molecules and co-stimulatory activity (B7
molecule)
 Macrophages : requires activation to up-regulate MHC-II molecules and co-stimulatory molecules (B7
molecules)
 B cells : always express MHC-II molecules but needs to be activated to express co-stimulatory activity
(B7 molecule)
30

31. Major Histocompatibility Complex (MHC)
• The MHC loci encode two major classes of membrane-bound glycoproteins: class I and class II MHC
molecules.
• They function as antigen-recognition molecules.
• TH cells recognize antigen combined with class II molecules, whereas TC cells generally recognize
antigen combined with class I molecules.
• MHC molecule can bind to a spectrum of antigenic peptides derived from the intracellular degradation of
antigen molecules.
• These variable regions form a cleft within which the antigenic peptide sits and is presented to T
lymphocytes.
31

32. • Foreign protein antigen are degraded into small antigenic
peptides that form complexes with class I or class II MHC
molecules.
• This conversion of proteins into MHC-associated peptide
fragments is called antigen processing and presentation.
• Whether a particular antigen will be processed and
presented together with class I MHC or class II MHC
molecules appears to be determined by the route that the
antigen takes to enter a cell.
32

33. Antigen processing and presentation
33

34. 1. Location of pathogen
- viruses in cytosol, MHC class I pathway, Tc response (Cytosolic pathway)
- extracellular bacteria, MHC class II pathway, Th2 response Ab formation (Endocytic pathway)
- intracellular bacteria, MHC class II pathway, Th1 response cellular response (Endocytic pathway)
2. Peptides derived from both self & non-self proteins can associate with MHC class I and class II
molecules.
3. Chemical nature of MHC groove determines which peptides it will bind.
4. MHC-I and MHC-II associated with peptides processed in different intracellular compartments
- Class I MHC binds peptides derived from endogenous antigens
- Class I MHC binds peptides from antigens that have been processed via the cytosolic pathway (derived
from the cytoplasm of the cell)
- Class II MHC molecules bind peptides derived from exogenous antigens. These antigens were
internalized by phagocytosis or endocytosis. 34

35. Processing of protein antigens
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al. 35

36. CLASS I MHC PATHWAY
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
Injected via Bacterial
secretory mechanisms
Phagocytosed
Escape Mechanism
36

37. Class I MHC Pathway
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
• Peptides are generated by
proteasome degradation
• Peptides are transported
from cytosol to the RER
• Peptides loading onto MHC-I
is aided by Chaperones
37

38. Class I MHC Pathway
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
38

39. TAP (Transporter associated with Antigenic Processing)
• Peptides from proteasome degradation of cytoplasmic proteins are
transported across the membrane of the rough endoplasmic
reticulum by a heterodimeric protein designated as TAP.
• TAP is composed of two subunits - TAP1 and TAP-2
• TAP-mediated transport is ATP-dependent
• The genes for TAP1 and TAP2 are encoded within the MHC
39

40. Class I MHC Pathway
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
Membrane Chaperone:
Calnexin
Luminal Chaperone:
Calreticulin
40

41. • 1. The class I alpha chain is stabilized by calnexin.
• 2. When the alpha chain binds beta-2-microglobulin:
- calnexin is lost
- calreticulin and tapasin bind
• 3. Tapasin & calreticulin brings the class I molecules into the vicinity
of the TAP.
• 4. A cytoplasmic peptide transported through the TAP is loaded onto
the class I molecule.
• 5. Class I MHC dissociates from calreticulin and tapasin. Class I
MHC-peptide complex is transported to Golgi and to the cell surface.
Assembly of the class I-peptide complex
41

42. Class I MHC Pathway
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al. 42

43. CLASS I MHC PATHWAY
43

44. Class II Processing:
• The endocytic antigen processing pathway
– processing of externally-derived peptides
• Antigen can be taken into cells by various
means: phagocytosis, endocytosis,
pinocytosis, receptormediated endocytosis
• Antigen taken up in these ways passes
through a series of intracellular
compartments of increasing acidity - early
endosome (pH 6.5-6.0), late endosome (pH
6.0-5.0), phagolysosome (pH <5.0).
44

45. • Three major events occur in the endosomal pathway:
1) Degradation of material that was taken in – endosome goes through acidification and fusion with
lysosome which contain a wide array of degradative enzymes
2) Loading of peptides from this material on to class II MHC molecules
3) Transport of class II MHC – peptide complexes back to the cell surface.
• The endosomal compartment is completely separate from the endoplasmic reticulum ---> So, externally
derived peptides are usually not loaded on to MHC-I.
45

46. Class II MHC Pathway
Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
Endosome-Lysosome
Phagolysosomes
Autophagosomes
46

47. Class II MHC is synthesized in the ER, but is not loaded with peptides there because it's peptide binding site
is blocked by the invariant chain (Ii).
STEP 1:
Cathepsins degrade
Invariant Chain

CLIP
STEP 2:
HLA-DM removes CLIP
47

48. • Once class II MHC enters the endosomal compartments, the invariant chain is degraded, leaving a small
fragment - CLIP - in the peptide binding site. CLIP is removed by HLA-DM, which loads a peptide on to
class II MHC HLA-DO inhibits HLA-DM until the cell is Activated
48

49. CLASS II PATHWAY
49

50. 50

51. 51

52. Role of antigen-presenting cells in periodontal diseases
• Various studies Konermann A 2012 in the past have suggested the role of APCs in the maintenance of
oral health as well as pathogenesis of periodontal diseases. APCs have a very important role in inducing
and maintaining mucosal immune homeostasis to harmless commensal bacteria and to self-antigens.
• They migrate in the immature state to various lymphoid organs and induce the antigen-specific
unresponsiveness or tolerance. Smits HH 2005
• In the process of transition from health to disease, the APCs induce a strong immune response under the
influence of various pro- and anti-inflammatory cytokines. Pulendran B, 2001
52

53. • The chemokines and their receptors control these cell movements through their molecular signals. The
expression patterns of the chemokines, and macrophage inflammatory protein 3 (MIP 3), and their respective
receptors CCR6 and CCR7, suggests that these molecules mediate influx of APC, especially DCs into the
tissues and efflux to T-cell rich areas in lymph nodes.
• Failure of migrating DCs to mature en route to lymph nodes or the ability of the DCs to depolarize cytokine
profiles toward a T helper type 2 (Th2) profile can lead to immune suppression.
• Porphyromonas gingivalis lipopolysaccharide (LPS) has shown to suppress the immunity thereby inducing
weak DC maturation and Th2 response.
• It is also observed that the resolution of the inflammation is dominated by the migration of fully matured DCs
from inflamed sites into lymph nodes leading to Th1 type cell-mediated immune response.
53

54. • After the DC migrates out of the periphery, monocytic DC precursors migrate in from the bloodstream and from
the bone marrow. DC precursors are also recruited in elevated numbers to infected sites by different
chemokines. These chemokines may have particular relevance to chronic periodontitis, which shows a dominant
Th2 response.
• Immature DCs that are activated at the site by pathogen-associated molecular patterns (PAMPs), in-turn
secrete chemokines that attract other inflammatory cells, including activated T cells, natural killer cells, and
additional DCs.
• The recent studies show that the human gingiva is infiltrated with large numbers of TLR 2 positive and TLR 4
positive cells, and that their numbers increase significantly in chronic periodontitis.
• The NACHT-LRR (domain present in NAIP, CIITA, HET-E, and TP1 with leucine-rich repeat) proteins or
nucleotide-binding oligomerization domains (NODs) have been identified on DCs that, like TLRs, possess the
capability to recognize microbes and convert this information to elicit appropriate downstream signaling
events.
54

55. • When the transition from gingivitis to periodontitis occurs,it is accompanied by a shift in lymphocyte
populations whereby T cells form the majority of lymphocytes in the inflammatory infiltrates in gingivitis
tissues, while there is an increase in the numbers of B cells and plasma cells in periodontitis lesions.
Seymour et al - 1979
• Different antigen-presenting cells (APCs) have been suggested to direct T cells to a Th1 or Th2 pathway,
possibly via presentation of different antigenic epitopes involving different second signals resulting in the
secretion of different cytokine patterns. Bloom et al - 1992
• Macrophage numbers do not increase and there is little evidence of macrophage activation in advanced
periodontitis compared with minimally inflamed tissues Chapple - 1998
• Consistent with this, it has been demonstrated that, in the progression from gingivitis to periodontitis,
there is a decrease in the macrophage/B-cell ratio Gemmel - 2000
55

56. 56

57. • Dendritic cells, Langerhans cells, and certain tissue macrophages are also equipped to capture
microorganisms and self-antigens by the expression of distinct sets of C-type lectin receptors.
• Many of the C-type lectin receptors are expressed in human gingiva, including the
Langerhans cell-specific marker Langerin (CD207),
macrophage mannose receptor (CD206),
DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN; CD209), with
Langerin decreasing in the gingival epithelium in chronic periodontitis, while the macrophage mannose
receptor and DC-specific intercellular adhesion molecule-3 grabbing nonintegrin increase in the lamina
propria in chronic periodontitis.
• The active lesions of periodontal disease harbor both mature and immature DCs located in different
compartments of the affected periodontal tissues surrounding bone.
57

58. • Moreover, DCs in the actively inflamed tissues of chronic periodontitis form aggregates with T cells,
where the DC/ T-cell interactions through receptor activator of nuclear factor-B-ligand
(RANK-RANKL) signaling take place.
• The DCs are thought to indirectly influence the periodontal bone loss through mediation of
inflammation, but recently it is seen that human peripheral blood monocyte-derived DCs can
transdifferentiate into osteoclasts in the presence of macrophage colony-stimulating factor and
RANKL in vitro, suggesting a direct involvement of DCs in osteoclastogenesis Theill LE 2002.
58

59. Conclusion
• The APC form a very vital component of the human immune mechanism.
• The role of the different APCs in the immune mechanism still needs more elaboration and research.
• The DCs play a central role in the immune response and its interaction with cytokines and T cells is an
important component of the immune cascade.
• The detailed understanding of the APCs, especially DCs, will help in developing the therapeutic strategies for
various inflammatory and autoimmune diseases.
59

60. References
• Cellular and Molecular Immunology 8th Ed. (2015) by Abbas et al.
– Chapter 6: MHC Molecules and Antigen Presentation to T Lymphocytes
60
• Antigen presenting cells in periodontal disease Neeraj Deshpande, Deepak Dave Indian Journal of
Oral Sciences Vol. 3 Issue 2 May-Aug 2012 69.
• Antigen Presentation and the MHC Herbert L. Mathews, Ph.D. Host Defense 2013
• Azuma M. Fundamental mechanisms of host immune responses to infection. J Periodontal Res
2006;41:361 73.
• Cutler CW, Teng YT. Oral mucosal dendritic cells and periodontitis: Many sides of the same coin with
new twists. Periodontol 2000 2007; 45:35 50.
• Cutler CW, Jotwani R. Antigen-presentation and the role of dendritic cells in periodontitis. Periodontol
2000 2004 ; 35:135 57.
• Cutler CW, Jotwani R, Palucka KA, Davoust J, Bell D, Banchereau J. Evidence and a novel hypothesis
for the role of dendritic cells and Porphyromonas gingivalis in adult periodontitis. J Periodontal Res
1999; 34:406 12.

61. • Antigen presenting cells in periodontal disease Neeraj Deshpande, Deepak Dave Indian Journal of Oral
Sciences Vol. 3 Issue 2 May-Aug 2012 69.
• Antigen Presentation and the MHC Herbert L. Mathews, Ph.D. Host Defense 2013
• Azuma M. Fundamental mechanisms of host immune responses to infection. J Periodontal Res
2006;41:361 73.
• Cutler CW, Teng YT. Oral mucosal dendritic cells and periodontitis: Many sides of the same coin with
new twists. Periodontol 2000 2007; 45:35 50.
• Cutler CW, Jotwani R. Antigen-presentation and the role of dendritic cells in periodontitis. Periodontol
2000 2004 ; 35:135 57.
• Cutler CW, Jotwani R, Palucka KA, Davoust J, Bell D, Banchereau J. Evidence and a novel hypothesis
for the role of dendritic cells and Porphyromonas gingivalis in adult periodontitis. J Periodontal Res
1999; 34:406 12.
61