(04) Cellular immunity and Histocompatibility Flashcards
Where are T-cells produced and where do they mature?
develop from a common lymphoid projenitor in bone marrow
migrate to the thymus (primary lymphoid organ) where they mature
where are B cells produced and where do they mature?
they are produced in the bone marrow (primary lymphoid organ) and migrate to the spleen / lymph nodes? to mature
What are the two types of T cells and what are the descriptors?
surface molecules CD4 and CD8
CD8+ = cytotoxic, 20%
CD4+ = helper, 80%
what do CD8+ T-cells do?
they kill cells by inserting pores - granzyme and perforins - so the contents leaks out
what do CD4+ T cells do?
produce cytokines
which drive the things that happen in immune response
name four subtypes of CD4+ T cells
Treg = regulatory T cell, dampens response
Th1 = drives cellular response
Th2 = drives antibody response
Th17 = regulate inflammatory response
when are both CD4 and CD8 molecules expressed on T cells?
Immature thymocyte
double positive
why is the thymus described as a primary lymphoid organ?
largest at birth, shrinks with age
responsible for developing T-cell repertoire
What is the general role of T cells?
distinguishing self and non-self
hence why tissue transplants are so difficult (tissue rejection)
what is tolerance / central tolerance?
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)
how to T cells distinguish a normal cell and a virally infected cell?
recognise differences in a set of polymorphic proteins called MHC
(major histocompatibility complex)
= the genetic locus expressed on ALL self cells
In humans, what do MHC genes code for?
proteins called human leukocyte antigens (HLA) on the cell surface
What is a CTL?
Cytotoxic T-cell
What change in MHC causes a reaction from T cells?
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
Describe genetic recombination during the meiosis phase
homologous chromosomes pair up to form a tetrad, then chromosomes cross over and exchange genetic material, resulting in new combinations of alleles
describe how congenic mice are created and what they show
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
what does the congenic mice experiment show
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
what are the two components of viral immunity?
SELF: antigens encoded by MHC
NON-SELF: antigens encoded by virus
What are T-cell receptors?
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)
What are HLA and what are the six types?
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
what is the most important structural part of the HLA molecule?
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)
what are the three main structural regions of the Class 1 HCL molecule?
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
what part of the Class 1 HLA is described as polymorphic?
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
what is the structural difference between class I and II HLA molecules?
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
What class of MHC does CD4 and CD8 T cells recognise?
CD4 = helper, recognise antigens in class II
CD8 = cytotoxic, recognise antigens in Class I
How do CD4 and CD8 initiate T cell signalling to activate adaptive immune response?
they both have intracellular tyrosine kinases associated with their cytoplasmic tails
initiate T-cell signalling through phosphorylation
how is the HELP function provided?
process
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
How is the KILLING function provided?
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
MHC Class I peptide source, pathogen, responding T cells, effector function
intracellular
viruses
CD8 responds
cytotoxic function
MHC Class II peptide source, pathogen, responding T cells and effector function
extracellular
Bacteria
CD4 responds
Help function
what is a marker of immune deficiency syndrome (eg. HIV, AIDS)?
population of CD4 T cells in blood decreases over time, to about zero
so the patient becomes susceptible to many types of pathogens
How is MHC polymorphism generated?
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)
what are two important consequences of MHC polymporphism?
- tissue transplantation v difficult (except in twins)
- commonly linked to autoimmune diseases
what is the purpose of MHC polymorphism?
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
