35. Cell-mediated immunity Flashcards
pathway of how T CELLS are formed (5 steps)
1.HAEMATOPOEITIC STEM CELLS in BONE MARROW
- DIFFERENTIATE into LYMPHOID PROGENITORS
- become PRO-T CELLS which MIGRATE TO THYMUS
- known as THYMOCYTES in thymus
- MATURE to become T CELLS
how do thymocytes MATURE to become T CELLS
- creating DIVERSITY within ANTIGEN BINDING REGIONS of T cell RECEPTORS
REARRANGE T cell ANTIGEN RECEPTOR GENES RANDOMLY to form unique antigen binding pocket
REARRANGE V (variable) D (diversity) and J (joining) GENE SEGMENTS RANDOMLY
for both ALPHA and BETA CHAINS
what is EDUCATION of T CELLS
many REACT STRONGLY with SELF ANTIGENS and are DELETED
all RECEPTOR proteins on any ONE LYMPHOCYTE (clone) have
the SAME EPITOPE SPECIFICITY
majority of T CELLS express a … T CELL ANTIGEN RECEPTOR
ALPHA BETA T cell antigen receptor
(alpha and beta chains)
- CD4+
- CD8+
approx 5% of T cells express which T-cell Receptor
gamma-delta
(very low number, unclear function)
T CELLS REQUIRE
ANTIGEN PRESENTATION on MHC molecules on antigen-presenting cells or virus-infected cells
- cannot recognise free antigens
CD8+ T CELLS recognise
ENDOGENOUS antigens (inside cell)
presented on MHC CLASS I
CD4+ T CELLS recognise
EXOGENOUS antigens (captures from outside cell)
presented on MHC CLASS II
T cells develop as Thymocytes in the Thymus and interact with…
STROMAL CELLS
which ACTIVATES them
- gives rise to ALPHA BETA T cells
what is CD3
common cell surface MARKER found on ALL T-Cells
what is an Immature DOUBLE-NEGATIVE THYMOCYTE
LACKS EXPRESSION of CD4 & CD8 RECEPTORS
subdivided into expression of CD44, CD25
DN4: EXPRESS BOTH CD44, CD25
DN3: EXPRESS CD25, LACK CD44
what is an Immature DOUBLE-POSITIVE THYMOCYTE
EXPRESS CD4 & CD8 RECEPTORS
rearrange t cell receptor alpha chain loci
migrate to thymus - mature
downregulation of either CD4 or CD8
what happens to T-Cells that REACT too STRONGLY to SELF-ANTIGENS or MHC
undergo APOPTOSIS
- DELETION
what on the T cell forms a COMPLEX to recognised the presented ANTIGEN
T-cell RECEPTOR
CD8/CD4
CD3
how do T and B CELL RECEPTORS have VARIABLE REGION - UNIQUE antigen-binding pocket
by VDJ RECOMBINATIONS
SIMILARITIES between T and B CELL RECEPTORS
-CONSTANT and VARIABLE regions
- 2 DIFFERENT CHAINS
DIFFERENCES between T and B CELL RECEPTORS
B CELL:
Recognise free antigen
Receptor SECRETED (antibodies)
T CELL:
Recognise MHC-bound peptides
Not secreted
what happens when T-CELLS ENCOUNTER specific presented ANTIGEN in lymphoid tissue
becomes ACTIVATED
undergoes PROLIFERATION : CLONAL EXPANSION
& DIFFERENTIATION into
EFFECTOR CELLS and MEMORY CELLS
T cell pathway
development - maturation - activation - action
- T-cell precursors migrate from bone marrow to thymus and REARRANGE its T-cell receptor genes
- VDJ Rearrangement - SELECTION - immature T-cells that recognise self-antigens too strongly are REMOVED.
only thymocytes with LOW AFFINITY to self-antigens/MHC MATURE - Mature T-cells exit thymus and encounter foreign ANTIGEN in lymphoid organs - ACTIVATED
- PROLIFERATION and DIFFERENTIATION to eliminate infection (as either CD4+ or CD8+)
FUNCTIONS of CD8 T-CELLS
- Detect and eliminate VIRUS-INFECTED CELLS before they can shed virus particles to infect other cells
- Recognise and kill “altered-self” cells e.g. TUMOUR CELLS
- Produce CYTOTOXIC MOLECULES that trigger APOPTOSIS
- RELEASE CYTOKINES (attract macrophages)
- Recognise foreign peptides bound to MHC CLASS I proteins
- Clonal expansion and differentiation into activated cells and memory cells
how do CD8 T CELLS DESTROY TUMOURS
INDUCE APOPTOSIS
presenting ANTIGEN on MHC CLASS 1 to Naïve CD8 T CELLS causes
CLONAL EXPANSION & DIFFERENTIATION into
ACTIVATED CYTOTOXIC T CELLS
& MEMORY CYTOTOXIC T CELLS
CD8 CYTOTOXIC T-cells ELIMINATE pathogen-infected cells by releasing
CYTOLYTIC GRANULE CONTENTS:
- PERFORIN
- GRANZYMES
- GRANULYSIN
FUNCTION of PERFORIN secreted by CD8 CYTOTOXIC T-cells to eliminate pathogen-infected cells
form PORES in MEMBRANE
of virus-infected target cell
FUNCTION of GRANZYMES secreted by CD8 CYTOTOXIC T-cells to eliminate pathogen-infected cells
cause APOPTOSIS
- activate CASPASES
FUNCTION of GRANULYSIN secreted by CD8 CYTOTOXIC T-cells to eliminate pathogen-infected cells
- contributes to APOPTOSIS
- has ANTI-MICROBIAL activity - stop virus reproducing in cell
what do CD8 CYTOTOXIC T-Cells also SECRETE
CYTOKINES
to ATTRACT MACROPHAGES
(eat up viral particles from apoptosis
- Degraded cells rapidly removed by macrophages)
CD4 HELPER T cells work largely by secreting..
CYTOKINES
-COMMUMICATE with other IMMUNE CELLS
and
ACTIVATE OTHER EFFECTOR CELLS to eliminate the pathogens by appropriate immune responses
CD4 HELPER T-Cells secrete DIFFERENT CYTOKINES by different..
Th SUBSETS
defined by the different cytokines they produce
once ACTIVATED, CD4+ HELPER T-cells….
DIFFERENTIATE into DIFFERENT SUBSETS
- secreting DIFFERENT CYTOKINES
CD4+ SUBSETS (4)
- TH1,
- TH2,
- TH17,
- T REG (t-regulator cell)
how do we get DIFFERENTIATION into DIFFERENT SUBSETS of CD4
- DIFFERENT CYTOKINES activate DIFFERENT COMBINATIONS of TRANSCRIPTION FACTORS
- Expression of DIFFERENT GENES
- DIFFERENTIATION of NAIVE CD4+ into different subsets TH1, TH2, TH17, Treg
Why is there such DIVERSE TYPES (SUBSETS) of HELPER T cells needed by our immune system?
Our body comes across MANY TYPES of PATHOGENS & infections
* Different target sites
* Different target cells
Specialised responses for each pathogen/target site required`
what do TH1 HELPER T cells respond to
Intracellular Infection - VIRUS
what is secreted by antigen-presenting cell to stimulate differentiation of TH1
IL-12
what does TH1 helper T secrete
IL-2
IFN-GAMMA (interferon gamma)
what does IL-2 secreted by TH1 HELPER T cells do
promote GROWTH & DIFFERENTIATION of other T CELLS
what does IFN-GAMMA secreted by TH1 HELPER T cells do (2)
- ACTIVATES of MACROPHAGES &
enhanced PHAGOCYTOSIS - UPREGULATES MHC EXPRESSION
(more easily recognised by T-cells)
TH1 HELPER T cells stimulate production of…
ANTIBODIES
(by secreting cytokines)
what do TH2 HELPER T cells respond to
PARASITIC infections
how do TH2 HELPER T cells KILL PARASITES
Stimulates B cells (class switch) for IgE
antibody production
Activates MAST CELLS and EOSINOPHILS to release TOXIC MOLECULES to kill parasites
TH2 HELPER T cells INDUCE PRODUCTION of..
MUCUS in INTESTINES
(Stop parasites penetrating through gut wall)
TH2 HELPER T cells SECRETE
IL-4
IL-5
IL-13
TH2 HELPER T cells differentiation from naive CD4 is activated by APC cells releasing
IL-4
what do TH-17 HELPER T cells respond to
infection by Extracellular BACTERIA or FUNGI
how do TH-17 HELPER T cells KILL infections by BACTERIA/FUNGI
IL-17 & IL-22 Stimulate ENDOTHELIAL CELLS,
FIBROBLASTS & MACROPHAGES
- to produce ANTIMICROBIAL PEPTIDES
& CYTOKINES (e.g. IL-6, IL-8, TNFa)
- INDIRECTLY RECRUITS NEUTROPHILS to
infection sites
(IL-8 from other cells which IL-17 binds to as human neutrophils dont have receptors for IL17)
what does APC release to stimulate DIFFERENTIATION of Naive CD4 into TH17 SUBSET
IL-6
TGF-GAMMA
what does TH-17 HELPER T cell release
IL-17
IL-22
what is the role of T REG HELPER T cells
come at END of infection to SWITCH EVERYTHING OFF
- TOLERANCE (resetting immune system)
BALANCE the PRO-INFLAMMATORY RESPONSE (by TH1,TH17, CD8)
SUPPRESS T cell RESPONSES & limit
inflammation
- Potent SUPRESSION of MACROPHAGE
function - Prevent auto-immunity
- Induces generation of more Treg cells
what does the role of Treg HELPER CELLS PREVENT by TOLERANCE
AUTO-IMMUNITY
what do T-REG HELPER T cells SECRETE to suppress T cell responses
IL-10
TGF-BETA
Recently recognised T cell subset : Follicular helper T cells (Tfh)
produce IL-21
critical for B cell differentiation & antibody-production
Reside in Germinal Centres (GC) of lymphoid tissues, closely associated with GC B cells
which CD4 HELPER SUBSET responds to PARASITES
TH2
help IgE antibody production
eosinophil and mast cell activation
which CD4 HELPER SUBSET responds to EXTRACELLULAR BACTERIA & FUNGI
TH-17
produce antimicrobial peptides & cytokines
& recruit neutrophils (by IL-8)
which CD4 HELPER SUBSET responds to VIRUSES
TH-1
macrophage activation
which CD4 HELPER SUBSET produces IL-17, IL-22
TH-17
which CD4 HELPER SUBSET produces IL-2, IFN-GAMMA
TH-1
which CD4 HELPER SUBSET produces IL-4, IL-5, IL-13
TH-2
which CD4 HELPER SUBSET produces IL-10, TGF-BETA
T REG
which CD4 HELPER SUBSET prevents auto-immunity
T-REG
which CD4 HELPER SUBSET IS stimulated by IL-12
TH-1
which CD4 HELPER SUBSET IS stimulated by IL-6 & TGF-BETA
TH-17
which CD4 HELPER SUBSET IS stimulated by IL-4
TH-2
