(L24) Cellular immunity, MHC and histocompatibility

Viruses are…

intracellular pathogens. They cannot grow by themselves but must use machinery inside the infected cell to replicate

Cellular immunity detects “flags” presented on the infected cell surface. These flags are…

molecules designed to pick up and present bits of virus to the immune system

It can also detect abnormal changes in cancer cells

The thymus

• Site of T cell development. Primary lymphoid organ largest at birth then shrinks with age - sits at the top of pericardium just above the heart

Haemopoietic lymphoid precursors migrate…

from the bone marrow to the thymus where they mature into T lymphocytes (T = thymus)

Only a small percentage of T cells survive the thymus and become…

mature peripheral T cells

The thymus is where your T cells learn not to react with your ______. This is called ____________ and is the first step in a crucial process called ___________ that keeps us all alive

own cell, thymic education, immune tolerance

Autoimmune disease is a consequence of the…

breaking of tolerance

T cells in the thymus become one of two main functional types

CD4 helper or CD8 cytotoxic

Immature thymocyte CD4+CD8+

CD8+, CD4+

CD8+

~20% in blood

CD4+ helper

~80% in blood

• Treg

• Th1

• Th2

• Th17

T cells rely on an important set of molecules to _____ whether a cell is ‘normal’ or ‘abnormal’ and what what type of ___________ is required

flag, immune response

These highly polymorphic proteins were first identified as controlling tissue transplantation. The gene complex coding for these molecules is called the…

Major Histocompatibility Complex (MHC)

Human MHC proteins are called…

Human Leukocyte Antigens (HLA)

T cells do not recognise antigens unless it is presented within…

MHC molecules

Histocompatibility

• T strains of mice (A and B) have different sets of MHC genes

• Transplanting skin from one mouse to the other results in graft rejection - same in humans

• Due to recipients T cells react to MHC molecules of donor tissues as “foreign” (non-self) and mount a powerful immune response destroying graft

• Reason why organ transplants are impossible unless MHC genes are carefully matches between donor and recipient - called tissue typing

Tissue transplantation, viral immunity and cancer immunotherapy all governed by…

histocompatibility - idea whether tissue will be accepted largely by MHC molecules

MHC polymorphism

• Everyone has same set of MHC genes, yet DNA sequences of genes varies between individuals

• Multiple MHC molecules exist, 6 main ones, and both maternal and paternal genes are expressed = 12 seperate MHC molecules for every persons cell (codominant)

• So extensive, two people rarely have exactly the same set of MHC genes

• Genetic polymorphism leads to amino acid variation in HLA molecules around the peptide binding cleft

• Reason why so hard to find a suitable donor for a transplant

MHC restriction

Viral immunity requires the immune system two antigenic components

• Self

• Non self

Self

Antigens encoded by MHC

Non-self

Antigens encoded by the virus

Molecules involved in MHC restriction

T Cell

• T cell Receptor (TcR)

• Peptide

• MHC (MLA) - Self

Target cell

T cell Receptor (TcR)

membrane bound Ig-like molecule on T lymphocytes. It’s genes also undergo gene rearrangement

Peptide

Antigen binding site of a TcR is formed in the same way as an antibody yet rightly restricted to MHC molecules. This restriction occurs during thymic education

MHC (HLA) - Self

Highly polymorphic HLA molecules are expressed on most cells and present peptide antigens to T cells

MHC Class I

has a single transmembrane proteins stabilised by B2 microglobulin

MHC Class II

Has two transmembrane chains (a and b) that form peptide binding cleft

CD4 and CD8 are accessory molecules on T cells that physically associate with the…

TcR/MHC/peptide complex

CD8

Cytotoxic T cells recognise peptides in MHC Class I

CD4

Helper T cells recognise peptides in MHC class II

CD4 and CD8 have ________ tyrosine kinases associated with their cytoplasmic tails that signal through ________. They are crucial to the _____ activation step of the _______ that leads to your __________ and steering it in the right direction

intracellular, phosphorylation, first, cascade, immune response

CD4+ helper T cells recognise peptides function

APC - HTL = HTL proliferate + release cytokines

Treg, Th1, Th2, Th17 are 4 important T helper subsets

recognises peptides presented by MHC class II on antigen presenting cells (APC) and proliferates into a helper cell phenotype that directs the the immune response (e.g. tells B cells to make antibodies or directs CTL to kill cancer cells or even to downregulate the immune response

Aids is caused by the loss of…

CD4 helper T cells that are killed by the HIV virus

CD8+ cytotoxic (CTL) function

recognises peptides presented by MHC Class I. Produces granny me and perforins that punch holes in the target cell membrane and destroy cell viability. Also kills by direct apoptosis.

Why has MHC evolved such polymorphism?

1. To be able to bind as many peptides as possible

2. To diversify a population’s response and survival to emerging pathogens

Unique HLA haplotypes are found in populations that have faced natural selection from regional pathogens.

This ensures that in a population, some individuals will be better equipped to survive the next pathogen

2 important consequences of MHC polymorphism

1. Tissue transplantation is difficult - requires HLA matching

2. Strongly linked to autoimmune diseases