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Flashcards in T cells Deck (20):
1

MHC Molecules

• Glycoproteins which are encoded by a set of closely linked genes in a region of the genome called the Major Histocompatibility (MHC) Complex (also known as HLA Complex)

• First identified by their effects in tissue transplantation
• When donor and recipient are of different MHC types then the recipient rejects
• Expressed on the surface of some cells where they display processed pep5des to T cells
• Two classes; MHC class I and MHC class II
• MHC class I expressed on ALL nucleated cells,
• Presents peptide from intracellular pathogens to CD8+ T cells
• MHC class II expressed on APCs, thymic epithelial, and activated T cells
• Presents peptide from extracellular pathogens to CD4+ T cells

2

Properties of MHC Molecules

MHC molecules are co-ordinately expressed
• All class I or all class II molecules are expressed on a given cell surface simultaneously

MHC molecules are highly polymorphic
• Multiple alleles of each MHC gene exist in different individuals

MHC molecules are co-dominantly expressed
• Both maternal and paternal MHC genes are expressed in same
cell

MHC Haplotype
• Combination of HLA alleles on a given chromosome 6

3

Processing of Exogenous Antigens

Taken in and processed in phagolysosome

CLIP protein put in place because instability
cd74 --> CLIP

through golgi apparatus Clip becomes Invariant chain

MHC class II assembled with ii

ribosomes come and synthesis indivisual MHC class II alpha and beta chains

released on surface to CD4 t cells

4

Processing of Endogenous Antigens

Virus infection, goes into cell, the viral protein is an endogenous antigen

The MHC class I has Beta-2 microglobulin chain with Alpha 1, 2, 3

Tap 1 and Tap 2 preptide transporters bring proteins to it

released on surface to CD8 t cells

5

characteristics of T cells

• Express surface receptors known as T-cell receptors (TCRs) which recognize peptide presented by MHC (dual recognition)
• Respond to antigens that have invaded the cell
• When activated, naïveT-cells proliferate and differentiate into effector or memory cells
• Function of effector T-cells is determined by cell surface expression of CD4 or CD8 Co-receptor
• T cells expressing CD4 recognize class II MHC molecules plus peptide
• T cells expressing CD8 are cytotoxic & recognize class I MHC molecules plus peptide
•Activated T cells produce and secrete cytokines which act on the cells that secrete them or different cells

6

TCR COMPLEX

Consists of:
Antigen binding region--
Variable region is where antigen binds
V alpha and V beta

CD3 complex:
on t cell surface, helps with recognition
Epilson, delta, epsilon, gamma

Itams: Help send signal

7

CD4 and CD8 Co-receptors

Transmembrane molecules expressed on T-cells Must bind MHC molecule for effective T-cell response Mature T cells express either CD4 or CD8 (not both) CD4 binds MHC class II
CD8 binds MHC Class I
Noncovalently associated with TCR and co-operate with TCR in recognition of peptide + MHC
Lowers dose of Ag required for activation by 100 fold
Intracellular portion interacts with kinases in cytoplasm and transduces activating signal

8

Receptor-ligand interactions on T cells and APCs

T CELL + APC

CD28 + B7: COSIGNAL
(works along side CD3 for signal transduction)

CTLA 4 + B7: INHIBITORY

PD-1 + PD-1L: INHIBITORY (ITIM)

LFA-1 + ICAM: ADHESION

9

Autoimmune Polyendocrinopathy-candidiasis ectodermal dystrophy (APECED)

• Autoimmune disease characterized by hypo-parathyroidism, candidiasis, adrenal insufficiency, hypogonadism, type I diabetes
• Recessive mutant AIRE genes •
AIRE gene
• Transcription factor that allows tissue specific genes to be expressed by thymic epithelial cells

10

T cell Maturation and selection in the thymus

1. Stem cell
2. Double neg cell (PRO-T CELL)
3. IL-7 induces proliferation
4. Pre-TCR (b chain rearragement & association w/ pre-t-alpha
5. Double positive (CD4+CD8+) immature t cell. functional alphabeta receptor

6. negative selection

6a. Weak recognition of class II MHC + peptide --> positive selection for mature CD4 T cell
6b. Weak recognition of class I MHC + peptide --> positive selection for mature CD8 T cell
6c. NO recognition of class I or II MHC + peptide --> failure of positive selection, death by neglect
6d. STRONG recognition of class I or II MHC + peptide --> negative selection

11

Positive Selection

by cortical epithelial cells in the thymus cortex

5. Double positive (CD4+CD8+) immature t cell. functional alphabeta receptor

12

Negative selection

of alpha-beta t cells by dendritic cells, macrophages, and other cells in the thymus medulla

6a. Weak recognition of class II MHC + peptide --> positive selection for mature CD4 T cell
6b. Weak recognition of class I MHC + peptide --> positive selection for mature CD8 T cell
6c. NO recognition of class I or II MHC + peptide --> failure of positive selection, death by neglect
6d. STRONG recognition of class I or II MHC + peptide --> negative selection

13

T Cell Dependent (TD) B cell Activation
(cognate interaction with T cell required)

• For a B cell to be activated by a protein antigen, it requires 2 signals
• Antigen provides signal 1
• T cell help provides signal 2
• Interaction with T cell co-stimulatory molecule, CD40L needed for 2nd signal
• T cell cytokines enhance 2nd signal

14

T independent response (TI)

Do not require T cell help to activate B cells

TI-1 response

• B cells activated by combination of signals through BCR
and TLR

TI-2 response

• Large polymeric molecules with repeating identical
polysaccharide subunits
• Activate B cells by extensively crosslinking mIg • Activate only mature B cells

15

Map Kinase Cascade RAS/RAC

AP-1 increased

16

IP3 cascase

increased intracellular Ca 2+
NF-AT

17

DAG cascase

NF-KB

18

Cyclosporin A (Cyclosporine) (CsA)

• Inhibitor of T cell mediated immunity

Generally:
Calmodulin binds calcineurin, which then can activate NFAT (neurotransmitter) to increase transcription of IL-2

Cyclosporin
• Inhibits production of IL-2 by activated T cells
– Binds to a cyclophillin and this complex binds to calcineurin and inhibits its phosphatase activity
– NFAT can not be dephosphorylated so it cannot move into the nucleus and turn on transcription of IL-2


• Used in organ transplantation, to treat psoriasis, & RA
• Adverse effects; nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity, hepatotoxicity

19

Tacrolimus (FK506)

– More potent than cyclosporine
– Binds to FK binding protein (FKBP) & this complex inhibits calcineurin so inhibits IL-2 production
– Appears to inhibit cell mediated immunity without inhibiting B cell or NK cell function
– Used for transplantation and as topical treatment for atopic dermatitis & eczema
– Adverse effect; Nephrotoxic

20

Sirolimus (rapamycin)

– Structurally similar to tacrolimus but has different mechanism of action

– Binds FKBP but blocks IL-2 R signaling needed for T cell proliferation (doesn’t inhibit calcineurin)

• Binds to and inhibits molecular target of rapamycin (mTOR), a serine threonine kinase that phosphorylates two proteins (PHAS-1 & p70S6 kinase) that regulates translation

• By inhibiting mTOR, it inhibits protein synthesis and arrests T cells in G1
– Inhibits kidney transplant rejection
– Adverse effects include; hyperlipidemia, leukopenia, and thrombocytopenia but not nephrotoxicity