Lecture 19 November 16 th 2010 Quiz 2 scheduled for November 23 rd not November 18th

New clues to effective HIV vaccine Created: Monday, November 08, 2010 Print Slight differences in five HLA amino acids may explain why certain people resist the human immunodeficiency virus, US researchers said in a study that lends new clues about how to make an Aids vaccine. "For a long time, we've known that some people progress extremely rapidly when they get infected, and others can stay well for three decades and never need treatment and still look entirely well," said Dr. Bruce Walker of Massachusetts General Hospital and Harvard University, whose study appeared online in Science. Specific amino acids in the human leukocyte antigen (HLA)-B peptide binding groove predicted protective and risk HLA alleles to persistent HIV infection.

In mice termed histocompatibility antigens (H-2 antigens). In humans termed human leukocyte antigens (HLA).

So how do MHC molecules work ? T helper and cytotoxic cells go around the body checking the pockets of the MHC molecules their TCR recognizes. If the pocket is empty they do nothing. If a CD8+ cells finds something in the pocket of a MHC 1 molecule it recognizes, it kills the cell bearing this MHC1. If a CD4+ cells finds something in the pocket of a MHC2 molecule it recognizes, it produces cytokines that can enhance immune functions of that cell and it can trigger the class switch if the cell is a B lymphocyte.

EMPTY

The pocket of a MHC 1 molecule can contain a fragment of antigen.

MHC1

What is eluted from a class 1 MHC ?

Peptides in MHC2 can slide across binding region to fit.

So how do peptides get into MHC1 and MHC2 class molecules? Class 1 molecules use the Endogenous pathway. Class 2 molecules use the Exogenous pathway.

No infection on a normal day…..

Normally MHC 1 assembled in RER and is unoccupied.

IN RER, MHC1 molecules are produced and assembled

What if cell becomes infected or altered ? Viral infection Bacterial infection Some normal cellular proteins Transformation

Endogenous Pathway

Endogenous Pathway using Ubiquination Pathway

If foreign antigens are in cell, tagged by ubiquitin and brought to proteosomes.

LMP2, LMP 7, LMP 10 are proteases associated with ~10% of proteasomes And produce peptide fragments 8-10 AA in length- perfect for MHC1 binding site. Small peptides migrate to Transporter-associated with antigen processing = TAP on RER.

MHC class 1 pathway Viral, tumor, bacterial protein

Precisely 8-10 AA in length

Third method of Cytotoxic T cell killing

First method of cytotoxic T cell killing of target cells

MHC 2 molecules on surface Everyday MHC 2 molecules produced and transported to the membrane of antigen presenting cells. What does this look like on a good day when there is no infection …..

B cell, Macrophage Dendritic cell not in the presence of antigen.

What if B cells binds antigen ? What if dendritic cell pinocytoses antigen ? What if macrophage phagocytosis antigen ? Antigen is internalized, processed and presented on the surface of the cell bound to MHC 2 molecules and can be recognized only by CD 4+ T helper cells

1ST 2nd B- lymphocyte as a antigen presenting cell

While in RER, MHC2 being made

While in the cell, antigen is being internalized

T cell receptor: T cells bind MHC class 1 molecules using CD8 and with a alpha beta TCR they search the peptide binding cleft. T cells bind MHC class 2 molecules using CD4 and with a alpha beta TCR they search the binding cleft. There are 2x the number of T h vs. T c. Endogenous pathway Exogenous pathway

T cell receptor: Never secreted. No somatic mutation. Of two types, Alpha –Beta chains (90- 99% of T cells) or Delta-gamma chains (1-10% )(few circulate, these T cells concentrated in gut)

Alpha chain encoded by a variable, J and constant region gene. Beta chain encoded by a variable, diversity, J and constant region gene.

D

How are T cell receptor types mutually exclusive? A productive arrangement of the alpha on chromosome 14 excises the delta chain gene segments which lie between the variable alpha genes and the J alpha genes.

T cells are MHC restricted. They only help or kill cells with whom they share MHC. Zinkernagel 1994

Helper T cells are also MHC restricted.

This work indicated that T cells recognize both MHC and specific antigen fragments. Does one receptor recognize the MHC and another receptor recognize the antigen fragment embedded in the binding site on the MHC ? Or is there one receptor with specificity for MHC in combination with a specific antigen fragment ?

Dual Receptor Theory

Experiment demonstrating the thymus selects this MHC specificity.

T cell differentiation in the thymus

T cell differentiation : How to explain MHC restriction and double the number of T helper cells compared to cytotoxic cells.

Rejection Mechanisms Rejection is an adaptive immune response and is mediated through both T cell mediated and humoral immune (antibodies) mechanisms. The number of mismatched alleles determines the speed and magnitude of the rejection response. Different grafts usually have a proclivity to a certain mechanism of rejection. Organ/tissue Mechanism Blood Antibodies (isohaemagglutinins) Kidney Antibodies, CMI Heart Antibodies, CMI Skin CMI Bonemarrow CMI Cornea Usually accepted unless vascularised, CMI

The pocket of a MHC 1 molecule can be empty or contain a fragment of antigen.

So how do MHC molecules work ? T helper and cytotoxic cells go around the body checking the pockets of the MHC molecules their TCR recognizes. If the pocket is empty they do nothing. If a CD8+ cells finds something in the pocket of a MHC 1 molecule it recognizes, it kills the cell bearing this MHC1. If a CD4+ cells finds something in the pocket of a MHC2 molecule it recognizes, it produces cytokines that can enhance immune functions of that cell and it can trigger the class switch if the cell is a B lymphocyte.

The pocket of a MHC 1 molecule can be empty or contain a fragment of antigen.