(04) Cellular immunity and Histocompatibility

Question 1

Where are T-cells produced and where do they mature?

Answer 1

develop from a common lymphoid projenitor in bone marrow
migrate to the thymus (primary lymphoid organ) where they mature

Question 2

where are B cells produced and where do they mature?

Answer 2

they are produced in the bone marrow (primary lymphoid organ) and migrate to the spleen / lymph nodes? to mature

Question 3

What are the two types of T cells and what are the descriptors?

Answer 3

surface molecules CD4 and CD8

CD8+ = cytotoxic, 20%
CD4+ = helper, 80%

Question 4

what do CD8+ T-cells do?

Answer 4

they kill cells by inserting pores - granzyme and perforins - so the contents leaks out

Question 5

what do CD4+ T cells do?

Answer 5

produce cytokines
which drive the things that happen in immune response

Question 6

name four subtypes of CD4+ T cells

Answer 6

Treg = regulatory T cell, dampens response
Th1 = drives cellular response
Th2 = drives antibody response
Th17 = regulate inflammatory response

Question 7

when are both CD4 and CD8 molecules expressed on T cells?

Answer 7

Immature thymocyte
double positive

Question 8

why is the thymus described as a primary lymphoid organ?

Answer 8

largest at birth, shrinks with age
responsible for developing T-cell repertoire

Question 9

What is the general role of T cells?

Answer 9

distinguishing self and non-self
hence why tissue transplants are so difficult (tissue rejection)

Question 10

what is tolerance / central tolerance?

Answer 10

T cells undergo a process of selection in the thymus to build tolerance to self

only 1% survive and make it out of the thymus as mature CD4/8+ cells (they have been “educated” by coming into contact with your MHC)

Question 11

how to T cells distinguish a normal cell and a virally infected cell?

Answer 11

recognise differences in a set of polymorphic proteins called MHC
(major histocompatibility complex)
= the genetic locus expressed on ALL self cells

Question 12

In humans, what do MHC genes code for?

Answer 12

proteins called human leukocyte antigens (HLA) on the cell surface

Question 13

What is a CTL?

Answer 13

Cytotoxic T-cell

Question 14

What change in MHC causes a reaction from T cells?

Answer 14

the MHC expresses a “neo-antigen” on the outside of the cell, picked up from inside the cell
(shape change of MHC molecule)
when the self peptide is replaced by a foreign peptide, T cells respond

Question 15

Describe genetic recombination during the meiosis phase

Answer 15

homologous chromosomes pair up to form a tetrad, then chromosomes cross over and exchange genetic material, resulting in new combinations of alleles

Question 16

describe how congenic mice are created and what they show

Answer 16

crossbreed mouse A and B, forming mouse AxB. if it has a B chromosome, has parts that are crossed over from A
backcross progeny with parental strain x20, end up with a B mouse
–> a means of detecting a genetic locus, which defines tissue rejection

Question 17

what does the congenic mice experiment show

Answer 17

after 20x backcrosses, the congenic AxB hybrid still rejects tissue from strain B
therefore the tiny genetic region that controls tissue rejection has come from A

Two congenic strains of mice were infected with a virus - cytotoxic T cells were isolated and ONLY killed infected cells of the SAME STRAIN
hence T cells control viral immunity

Question 18

what are the two components of viral immunity?

Answer 18

SELF: antigens encoded by MHC
NON-SELF: antigens encoded by virus

Question 19

What are T-cell receptors?

Answer 19

a membrane-bound immunoglobin-like molecule on T lymphocytes that are responsible for recognising peptides bound to MHC
(they make contact with the surface of the MHC molecule)

Question 20

What are HLA and what are the six types?

Answer 20

Human Leukocyte Antigens, a type of protein expressed on human cells
it is a FORM of the MHC gene complex SPECIFIC TO HUMANS!!!

six types in 2 classes:
Class I = A, B, C
Class II = DR, DP, DQ

Question 21

what is the most important structural part of the HLA molecule?

Answer 21

the distal end, furthest from the membrane, called the peptide groove
alpha helices and flat floor, containing the viral peptide (normally occupied by self peptide)

Question 22

what are the three main structural regions of the Class 1 HCL molecule?

Answer 22

distal region - the bit we’re interested in, has the peptide
the constant region (closest to membrane)
Beta-2-microglobulin - off the side, keeps the whole molecule very STABLE so once something is picked up it is expressed on the cell surface for a very long time

Question 23

what part of the Class 1 HLA is described as polymorphic?

Answer 23

the distal region with the peptide binding cleft (the two alpha helices and the floor)
bc it is different between different people
a massive range of amino acids expressed in the region

Question 24

what is the structural difference between class I and II HLA molecules?

Answer 24

Class I has a single heavy chain
Class II has two chains: alpha and beta

same peptide binding groove, except in class II the ends are open so longer peptides can fit

Question 25

What class of MHC does CD4 and CD8 T cells recognise?

Answer 25

CD4 = helper, recognise antigens in class II
CD8 = cytotoxic, recognise antigens in Class I

Question 26

How do CD4 and CD8 initiate T cell signalling to activate adaptive immune response?

Answer 26

they both have intracellular tyrosine kinases associated with their cytoplasmic tails
initiate T-cell signalling through phosphorylation

Question 27

how is the HELP function provided?
process

Answer 27

when pathogen is extracellular (eg. bacteria) and need to be taken up by phagocytic cells etc
bits of the bacteria broken down –> peptides

TcR/CD4/MHC class II + bacterial peptide complex presents on the surface of the cell
CD4 helper T cell responds, by PRODUCING CYTOKINES

Question 28

How is the KILLING function provided?

Answer 28

for intracellular viruses - viral proteins expressed on surface of cell
TcR/CD8/MHC class + viral peptide complex forms

CTL produces granzyme and perforins, punch holes in cell membrane

Question 29

MHC Class I peptide source, pathogen, responding T cells, effector function

Answer 29

intracellular
viruses
CD8 responds
cytotoxic function

Question 30

MHC Class II peptide source, pathogen, responding T cells and effector function

Answer 30

extracellular
Bacteria
CD4 responds
Help function

Question 31

what is a marker of immune deficiency syndrome (eg. HIV, AIDS)?

Answer 31

population of CD4 T cells in blood decreases over time, to about zero
so the patient becomes susceptible to many types of pathogens

Question 32

How is MHC polymorphism generated?

Answer 32

MHC amino acid sequence varies greatly!

individual expresses both maternal and paternal genes, which are CO-DOMINANT, so
2x3 MHC Class I and 2x3 MHC class II –> total of 12 polymorphic molecules expressed on cells

(each MHC receptor can bind to millions of peptide molecules)

Question 33

what are two important consequences of MHC polymporphism?

Answer 33

1. tissue transplantation v difficult (except in twins)
2. commonly linked to autoimmune diseases

Question 34

what is the purpose of MHC polymorphism?

Answer 34

to defend the population against new pathogens!

eg. with covid - some people more resistant than others
by selection, you get a population that has the most resistance to new pathogens