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Cellular immune responses
T Cell Subsets
• CD8/CTL• CD4/TH cells
1) TH1 - inflammatory response
2) TH2 - anti-inflammatory, B cell response
3) Treg - inhibit immune responses
Th1 express CCR5, CXCR3+ and Th2 express CCR4 and CCR8+
CD4+ Subsets: TH1 vs. TH2• Highly investigated in mouse model of
leishmaniasis: C57BL/6 mouse cures, but Balb/c mouse dies of uncontrolled infection
• Strains differ in cytokine responses• Resistant mice produce interferon- (IFN-),
tumor necrosis factor- (TNF-), and lymphotoxin, which activate inflammatory response and cell-mediated immunity: TH1
• Susceptible mice produce interleukin (IL)- 4, 5, 13, which are anti-inflammatory and promote B cell activation and antibody production: TH2
TH1 vs. TH2 Differentiation Depends on Cytokine Milieu
• TH1 differentiation is driven by the APC-derived cytokine IL-12
• TH2 differentiation is driven by the T cell-derived cytokine IL-4
• IL-12 and IL-4 are mutually antagonisitic: IL-12/IFN- inhibit IL-4 secretion and vice versa, leading to strongly polarized response
Mechanisms of Cytotoxicity
• CTL (but not naïve CD8+ T cells) express lytic granules: perforin, granzymes, granulysin
• Perforin lysis of target cell (inefficient)• Granzyme activation of cytosolic apoptosis
machinery• Fas/FasL induction of apoptosis
CD8 Cytotoxic T cell
MHC Class I
+
CD28
MHC Class II
Dendritic Cell
CD4+ T-cell Help for CD8+ CTL Mediated Through Activation of Dendritic Cell
CD40
CD4+ Helper T cell
CD40L
TCR
TCR
B7 costimulator
IL-15IL-12
IL-15 with vaccine
TFH is non-polarized T cell and Th1, Th2 cell polarize B cells.
Tpath
TpathTpath
Teff
TeffTeff
Teff
Teff
Treg
Treg
Treg
mDC
mDC
Teff
Teff
Teff
iDC
Treg
Tpath
mDC
Treg
Tpath
Teff
ProliferationNo suppression
APC
mDC mDC
Tmem†
Treg Treg
TpathTpath
Treg
Teff
Teff
Teff
TpathTpath
Treg
Treg
APC
A) Steady State: LN
B) Response phase: LN
C) Regulatory phase
LN
InflammatorySite
Tpath
+TLR+TLR
IL-6IL-6
IL-2IL-2
IL-10IL-10
IL-10IL-10
IL-10IL-10
TGF-TGF-
GITR-LGITR-LCD28CD28
Regulatory T Cells
• Long and spotty history of study: “suppressor” cells, “veto” cells, “infectious tolerance”, and now “regulatory” T cells
• Basic premise: one or more populations of T cells act to inhibit the responses of other T cells
Regulatory T Cells cont.
• Sakaguchi and colleagues found that thymectomy in <3 day-old mouse results in multiorgan autoimmunity
• Identified population of CD4+CD25+ T cells that restore self-tolerance
• Differentiation into Treg requires expression of FoxP3 (scurfin)
• Suppression of responses by both contact-dependent (inhibition of APC) and cytokine (IL-10, TGF-) mechanisms
HISTORICAL PERSPECTIVE of T regHISTORICAL PERSPECTIVE of T reg1970’s - existence of specialized suppressor T cells postulated1970’s - existence of specialized suppressor T cells postulated
- usually attributed to Lyt2- usually attributed to Lyt2++ (CD8 (CD8++) T) TSS cells cells
- variety of suppressive phenomena and networks- variety of suppressive phenomena and networks
1980’s - advent of molecular immunology1980’s - advent of molecular immunology
- inability to identify cellular and molecular mechs of suppression- inability to identify cellular and molecular mechs of suppression
- stigma associated with T- stigma associated with TSS cells cells
1990’s - phenotypic identification of CD41990’s - phenotypic identification of CD4++ T cell subsets T cell subsets
- distinct patterns of cytokine secretion Th1, Th2 etc.- distinct patterns of cytokine secretion Th1, Th2 etc.
- immunomodulatory roles for cytokines- immunomodulatory roles for cytokines
1994-present - rebirth of suppressor T cells as regulatory T1994-present - rebirth of suppressor T cells as regulatory TRR cells cells
- phenotypic and functional characterization of T- phenotypic and functional characterization of TRR cells cells
- role in preventing autoimmunity and immune pathology- role in preventing autoimmunity and immune pathology
Th3
Tr1
CD4
TGF- MHC class II-restricted
IL-10 (& TGF-MHC class II-restricted
TCR
Regulatory/Suppressor T cells
TReg
CD25 (IL-2R)
Ts
CD8
? Qa-1-restricted
TCR
IFN-IL-4, IL-13CD1d-restrictedNKTNK1.1
Contact inhibition MHC class II-restricted
CD4
IL-10
Naturally-occurring versus inducible TNaturally-occurring versus inducible TR R cellscells
TGF-?
Periphery
ALTERNATIVE FORM OF T-CELL RECEPTOR
• Second type of receptor consists of– Gamma and Delta chains
• T-cells referred to as– Gamma:Delta T-cells
• Gamma:Delta T-cells– Comprise approximately 1 to 5% of circulating T-cells– Function is unknown– Not restricted to MHC presentation of peptide antigens
• Alpha:Beta and Gamma:Delta receptors never expressed together
T-lymphocyte epitope-specific receptor
• Similarities with the Fab portion of a BCR/antibody– Two identical length chains (ά and β)– One antigen-binding site/receptor (one Vά and one Vβ)
– Cά and Cβ
– Beta sheets, intersheet bonds (non-covalent & disulfide)– Domains– HV and FR amino acid sequences
26
-MHC
TCR
CD4 CD8
TCR complex
Co-Receptor
CD28 Co-Stimulator
Integrine Adhesion molecule
MHC II / MHC IRestriktion
“Signal 2”
T cell receptor
Acc
e ss o
ry (
Hil
fs-)
Mo
l ek ü
le
CD3
28
Struktur
Monomer
Heterodimer
3. CD4 und CD8 Co-Rezeptoren
Ig-Superfamilie
CD8 Homodimere kommen ebenfalls auf bestimmten T Zell Populationen vor
29
2. CD3 und Proteine
Expression des TCR Komplexes erfordert alle seine Komponenten
Self MHC limitation
“Immunologische Synapse”
15 nm
Fig 9.6 p249
Fig. 8.12 T-cell activation through the T-cell receptor and CD28 leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules.
CTLA-4: Putting on the Brakes
1) CTLA-4 is another CD28-related receptor, and binds both B7-1 and B7-2 - avidity is at least 20x as high as CD28
2) CTLA-4 expression on the surface is undetectable in resting T cells, but is rapidly increased after TCR + CD28 signaling
3) Unlike CD28, CTLA-4 is inhibitory, and blocks T cell proliferation and IL-2 production - combination of competing B7 molecules away from CD28 and bona fide inhibitory signals (possibly phosphatases, but still not well defined)
CD28: The First (and still the champ!) Co-stimulatory Molecule
1) Yet another member of the immunoglobulin superfamily (single Ig-V domain)
2) Expressed on the surface of almost all T cells (100% of mouse T cells, ~80% of human T cells) as a disulfide-linked dimer
3) Binds to B7-1 (CD80) and B7-2 (CD86) expressed on antigen presenting cells
4) Cytoplasmic tail has binding motifs for several signaling molecules (PI3K, Grb2, Itk), but no ITAM. It is still unclear what signals CD28 contributes to T cell activation
5) Signaling by CD28 alone does not stimulate T cells, and only activates PI3K
Polarization of T Cells Part I: The Cytoskeleton
1) T cell responses are directed at the APC/target cell, not in all directions2) This requires reorganization of the cell to have a “front” (toward the APC)
and a “back” - induced by signals from the TCR and costimulatory molecules
3) Result: Reorganization of the cytoskeleton causes reorientation of cytosolic organelles toward APC - Golgi, secretory vessicles, and microtubule organizing center (MTOC). The MTOC connects actin cytoskeletal changes with the tubulin cytoskeleton
Fig. 8.29 The polarization of T cells during specific antigen recognition
The MHC molecules
• Class I– ά chain forms the peptide-binding “groove”– β-2 microglobulin provides stability
• Class II– ά and β chains form peptide-binding “groove”
• TCR binds to peptide• CD binds to MHC
MHC Class I antigen processing and presentation
• Peptides in cytoplasm– viral proteins– Tumor proteins (phenotypic expression of activated oncogenes)– Self-proteins (damaged, no longer needed, excess)
“Cross-presentation” by Dendritic Cells• Usual endocytosis of bacteria, soluble antigens
– Class II presentation as expected (peptides in membrane-bound vesicles)• Infection by viruses
– Class I presentation as expected (peptides in cytoplasm)
• DC involved in “priming” T-cells in lymph node– Need to present peptides using MHC Class II and Class I– Class II using “normal” endocytosis into membrane-bound vesicles– Class I presentation
• Endocytosis of viruses (not an infection)• Peptides moved into cytoplasm (Class I presentation)• Viral peptides also transferred to other DCs (into cytoplasm) to be presented by MHC Class I