Immunity cells

1. Immunology lectures 6
Dr./Instructor: Jama Raan (MBBS)
At University Of Burao
2021. 2. 14

2. The Processing And Presentation Of Antigen
• What Should We Want To Know About The Processing And
Presentation Of Antigen?
• How The grooves Of Class I and II MHC are loaded with peptides
• The three signals required for T-cell activation (TCR binding,
costimulatory molecules, and cytokines)
• How superantigens act
• The subclasses of T helper (TH) cells, their function and regulation

3. Endogenous Pathway.
• MHC molecules are designed to bind small peptides and present them to T cells.
• The class I molecule is synthesized in the endoplasmic reticulum of the cell and
proteins are loaded there by an Endogenous Pathway.
• Proteins are synthesized in the cell cytosol are routinely degraded in
proteasomes, and the peptides from these proteins and transported through a
peptide transporter, known as the TAP complex into the endoplasmic reticulum,
where they have the opportunity to bind to freshly synthesized MHC class I
proteins.
• These are then transported to the cell membrane where they may be presented
to CD8+ T lymphocytes.

4. Continue...
• Although some small, easily digestible antigens are almost totally degraded as
exocytosed by phagocytes, as we saw in the last chapter, the critical first step in
the elicitation of the adaptive immune system response to a first antigenic
challenge is the processing of such antigen for the presentation to naive T
lymphocytes.
• Professional antigen-present cells (dendritic cell, macrophages) load partially
degraded peptides they have ingested into the groove of the class II MHC
molecules, so that this can be presented to T cells with idiotypes
complementary to that struture. this is accomplished by the endosomal
(exogenous) pathway of MHC loading...

5. Antigens recognized by T lymphocytes.
• The majority of T lymphocytes recognize peptide antigens that are bounded to
and displayed by major histocompatibility complex (MHC) molecules of antigen
present cells.
• The MHC is a genetic locus whose principal protein products function as the
peptide display molecules of the immune system.
• In every individual, different clones of CD4+ and CD8+ T-cells can see peptides
only when these peptides are displayed by that individual's MHC molecules.
• This property of T cells is called MHC restriction.

6. Capture of protein antigen by antigen-present
cells.
• Protein antigen of microbes that enter the body are captured mainly by
dendritic cells and concentrated in the peripheral lymphoid organs, where
immune responses are initiated.
• Microbes usually, enter the body through the skin (by contact), the
gastrointestinal tract (by ingestion) and respiratory tract (inhalation). some
insect-borne microbes may be injected into the bloodstream as a result of insect
bite, and some infections are acquired through the genitourinary tract.
microbial antigens can also be produced in any infected tissue.
• It would be impossible for lymphocytes to patrol all these sites searching for
foreign invaders; instead, antigens are taken to the lymphoid organs through
which lymphocyte recirculate.

7. Continue...
• All the interferes between the body and the external environment are lined by
continuous epithelia, whose principal function is to provide a barrier to
infection.
• The epithelia and subepithelia tissues contains a network of dendritic cells; the
same cells are present in the T cell-rich areas of peripheral lymphoid organs and
in smaller numbers, in most other organs. there are two major populations of
dendritic cells, called convenational and plasmacytoid, which differ in their
locations and responses the majority of dendritic cells in tissues and lymphoid
organs belong to the conventional subset.

8. Continue....
• When MHC class II molecules are produced in the endoplasmic reticulum of an
antigen-present cell (APC), in addition to the α and β chains a third chain called
the invariant chain is synthesized at the same time. this block the peptide-
binding grooves so no normal cellular peptides can accidentally be attracted
there. as the molecule is completed, it is transported in a vesicle to the location
of endocytic vesicles containing the ingested internalized peptide.

9. Conti....
• As they fuse, the invariant chain is degraded, and peptide in the
vacuole are loaded into the MHC II groove.
• The MHC class II-peptide complex is then transported to the cell
surface where it will be accessible for interaction with any T
lymphocyte with a complementary TCR.

10. Table of dendritic cells
Feature Conventional DC Plasmacytoid DC
Surface marker CD11c high
CD11b high
CD11c low
CD11b negative
B220 high
Major location Tissues Blood and Tissue
Expression of TLR TLRs, 4,5, 8 high TLRs 7, 9 high
Major cytokines produced TNF, IL-6, IL-12 Type I interferons
postulated major functions Induction of T cell responses against
most antigens
Antiviral innate immunity and induction
of T cell rsponses against viruses.

11. Continue....
• Interluekin-1 (IL-1) the combination of TLR signaling and cytokines activates the
dendritic cells, resulting in several changes in phenotype migration and function.
• When conventional dendritic cells that encounter microbes at epithelial barriers
are activated, they lose adhesiveness for epithelia and begin to express the
chemokine receptor (CCR7) which is specific for chemoattracting cytokines
(chemokines) produced by lymphatic endothelium and by stromal cells in the T
cell zones of lymph node.

12. Conti....
• These chemokines direct the dendritic cells to exit the epithelium and
migrate through lymphatic vessels to the lymph nodes draining that
during the process of migration the dendritic cells mature from cells
designed to capture antigens into APCs capable of stimulating T
lymphocytes.

13. Continue.....
• Different types of APC serve distinct functions in T cell-dependent
immune response.
• It's estimated that if microbial antigens are introduced at any site in
the body, a T cell response to these antigens begin in the lymph node
draining that site within 12 to 18 hours...

14. Processing Of Exogenous Antigen.

15. Continue....

16. Continue....

17. Human MHC summary
Names HLA-A, -B, -C HLA-DP, -DQ, -DR, HLA-DM*
Tissue Distribution All nucleated cells, platelets B lymphocytes, monocytes,
macrophages, dendritic cells,
langerhans cells, activated T cells,
activated endothelial cells
Recognized By Cytotoxic T cells (CD8+) TH cells (CD4+)
Peptides Bound Endogenously synthesized Exogenously processed
Function Elimination Of Abnormal (Infected)
Host Cells By Cytotoxic T cell
presentation of foreign antigen to TH
cells
Invariant chain No Yes
β2 microglobulin Yes No
MHC Class I MHC Class II

18. Continue....
• Within a few hours of the initiation of the acute inflammatory responses by the
breaking of the mucosa or epithelia, the professional APCs that have
phagocytosed and processed the invading antigen begin to leave the area via
lymphatic vessels.
• dendritic cells, with their long, finger-like processes, are probably the most
efficient of these cells and retract their membranous processes to round up and
begin the journey to the closest lymph node.

19. Continue....
• Thus, phagocytes with MHC class II molecules loaded with peptides digested
from the invading antigen enter the lymph node through the afferent lymphatics
and become trapped in the network of the organs.
• The secondary lymphoid organ ( lymph node, and spleen) are the sites where
naive, recirculating lymphocytes will first be exposed to their specific organs.
• absence of spleen or functional asplenia (sickle cell aneamia) makes patients
exceptionally susceptible to encapulated bacteria or blood-borne pathogens.

20. Figure of APC and MHC

21. Continue.....
• The binding of the TCR of the naive T cell to the MHC class II-peptide complex of
the APC provides the first signal to the T cell to begin it's activation.
• This gives the antigenic specificity of the response. costimulatory molecules on
APC bring to second signal, and cytokines secreted by APC and the activating T
cells themselves induce the proliferation (clonal expansion) and differentiation
of the T cells into effector cells and memory cells.
• Several costimulatory molecules are involved in the activation of naive T
lymphocytes:

22. Continue....
• CD4 and CD8 (coreceptors for MHC class II and I respectively) transduce
activating signals to the T cells.
• Integrins on T-cells (LFA-1) binding to IgCAMs on APCs (ICAM-1) to increase cell-
cell adherence.
• Pathogen binding to innate receptors (e.g, TLR molecules) along with antigen
recognition triggers upregulation of B7.
• IgCAMs on T cell (CD2) bind to integrins (LFA-3) on APCs to promote cell-cell
adherence.
• CD28 on T cells binds to B7 on APCs and triggers the transcription of several
cytokine genes.

23. First, second and third signals....
• T-cell activation first signal binding TCR to MHC II/peptide complex..
• second signal (costimulatory molecules):
 CD4, binds MHC II
 CD8, binds MHC I
 LFA-1, binds ICAM-1
 CD2, binds LFA-3
 CD28 binds B7
• Third signal (cytokines)
A. IL-2
B. IL-1
C. IL-6
D. TNF- α

24. Continue....

25. Effectors mechanisms
• The activated CD4+ (Helper) T lymphocytes, which have thus been generated in
the lymph nodes and spleen following antigen administration, and now ready to
serve as the orchestrators ( arrange ) of virtually all the possible Effectors
mechanisms that will rise to destroy the antigenic invaders.
• The effectors mechanisms that are controlled totally or atleast in party by Th
cells include antibody synthesis, macrophage activation, cytotoxic T-cell killing,
and Natural killer cells killing.
• There are two major and two minor classes of helper T (TH) cells, both of which
arise from the same precursor the naive Th lymphocyte, sometimes called the
TH0 cells.

26. How Superantigens Act.
• superantigens are viral or bacterial proteins that cross-link the variable β
domain of a T-cell receptors to an α chain of a class II MHC molecule.
• This cross-linkage provides an activating signal that induces T-cell activation
and proliferation, in the absence of antigen-specific recognition of peptides
in the MHC class II groove. because superantigens bind outside of the
antigen-bind cleft, they activate any clones of T cells expressing a particular
variable β sequence and thus cause polyclonal activation of T cells,
resulting in the overproduction of IFN- γ.
• E.g, staphylococcal enterotoxins, toxic-shock syndrome toxin-1 (TSST-1).

27. How Superantigens Act
• The patern of differentiation is determined by the stimuli present early in the
immune response, at the site of antigen production.
• Differentiation of a TH0 cells into a TH1 cell seems to be stimulated by microbes
that stimulate a strong initial innate immune response with the resultant
production of IL-12 by macrophages or IFN-γ by a NK cells.
• The differentiation of TH1 cells is stimulated by many intracellular bacteria such
as Listeria and mycobacteria, and by some parasites e.g, Leishmania- All of which
infect macrophages.

28. Continue....
• The IFN-γ produced by TH1 cells promote further TH1 development and inhibits
the proliferation of TH2 cells; IL-4 and IL-10 produced by TH2 enhance TH2
differentiation and stops the activation of TH1 cells.
• The third population of T cells which arise from the TH0 is called the T-reg,
these cells regulate (inhibit) TH1 cell function.
• They secrete inflammatory inhibiting cytokines such as IL-10 and have been
shown to be critical for the prevention of autoimmunity

29. The subclasses of T helper (TH) cells, their
function and regulation
• The final one of TH cells which originates from the TH0 is known the TH17 cell.
• These cells are indentified by the expression of transcription factor RORgammat
and by their production of the proinflammatory cytokines IL- 17.
• They are believed to play a role in the tissue damage associated with some
autoimmune diseases.
• The effector mechanisms stimulated by the different classes of TH cells are
specialized to optimally destroy different classes of invading antigens and are
roughly (and somewhat artificially), divided into cell-mediated or humoral
effector mechanims.
• RORgammat is member of the nuclear receptor family of transcription factors.

30. Subsets Of Helper T Cells

31. The processing and presentation of antigen.

32. •Thanks To All