Bi1_2009_Lecture20_full - Two types of T cells • Killer T...

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Unformatted text preview: Two types of T cells • Killer T cells. Also called cytotoxic T lymphocytes (CTLs) – Coreceptor: CD8 – Recognize antigen bound by class I MHC molecules – Can kill virally-infected cells • Helper T cells (TH cells) – Coreceptor: CD4 – Recognize antigen bound by class II MHC molecules – Secrete cytokines that affect other immune system cells; e.g., they activate macrophages and help B cells make antibody • For completeness, but not for Bi1, there are also Regulatory T cells (Treg cells) To understand T cells, we have to understand the MHC proteins that present antigens to TCRs Major Histocompatibility Complex (MHC) • First discovered by tumor immunologists working with inbred mice. • Grow tumors by passaging them in mice. Tumors will only grow in the genetic strain they came from. Rejection of tumors results from differences in normal cellular antigens • The antigens causing tumor rejection are polymorphic. Polymorphic: genes different between individuals. Each variant of a gene called an allele. • Genes responsible for acceptance or rejection of tumors defined as histocompatibility genes -encode cellular structures that are polymorphic within species but immunogenic enough to evoke a rejection reaction. • Genetic region that determines graft rejection is called major histocompatibility complex (MHC). • The MHC encodes proteins (MHC class I molecules) that determine the acceptance or rejection of a graft. • Differences between foreign and self are due to genetic polymorphisms among different histocompatibility alleles. • Human MHC molecules are called “Human Leukocyte Antigens” (HLA). – Human MHC class I molecules are encoded in three loci: HLA-A, HLA-B and HLA-C – Different alleles of HLA are numbered: e.g., HLA-A1, HLA-B27, HLA-C3 – Within the human population, there are hundreds of possible HLA-A alleles, hundreds of HLA-B alleles, and hundreds of HLA-C alleles Clicker question MHC polymorphism is the result of: 1) 2) 3) 4) Differential (alternative) RNA splicing Gene recombination at the DNA level (as in antibodies) Mutation throughout the lifetime of an individual Inherited genetic differences Clicker question There are hundreds of different of HLA-A alleles, hundreds of HLA-B alleles, and hundreds of HLA-C alleles. What is the maximum number of different class I MHC proteins that any one individual can express? One Three Six Twelve Hundreds Millions 1) 2) 3) 4) 5) 6) Loci encoding human class I MHC proteins are HLA-A, HLA-B, & HLA-C Your class I MHC proteins: HLA-A2, -A8, -B5, -B27, -C3, -C3 My class I MHC proteins: HLA-A2, -A28, -B6, -B48, -C2, -C8 At least 100 alleles in human population at each locus. MHC genes are most polymorphic genes in genome of every species analyzed. Clicker question You need an organ transplant so you want to find a donor who is most closely matched to your HLA haplotype.* In the absence of knowing your HLA haplotype or anyone else’s, from which of the following people is it safest for you to obtain a donated organ? 1) 2) 3) 4) 5) 6) Your mother Your father Your fraternal twin One of your other siblings Your roommate Your Bi1 TA * Your set of HLA proteins: e.g., HLA-A2, -A8, -B4, -B7, -C1, C8 plus your class II MHC molecules -- more about these later. Your mother HLA-A2, HLA-Aw68 HLA-B5, HLA-B27 HLA-Cw1, HLA-C4 Your father HLA-A28, HLA-A44 HLA-B53, HLA-B55 HLA-Cw7, HLA-C18 Note 1: the scenario in which you are a perfect match with one of your siblings and completely mismatched with another is theoretically possible, but unlikely. You HLA-A2, HLA-A28 HLA-B27, HLA-B53 HLA-C4, HLA-C18 Note 2: Class I MHC molecules are expressed on all nucleated cells. Each cell expresses all class I molecules, not a subset. Sibling 1 HLA-Aw68, HLA-A44 HLA-B5, HLA-B55 HLA-Cw1, HLA-Cw7 Sibling 2 HLA-A2, HLA-A28 HLA-B27, HLA-B53 HLA-C4, HLA-C18 Clicker question Why does a woman tolerate a fetus? 1) 2) 3) 4) 5) 6) The fetus has the same MHC molecules as its mother. Half of the fetus’ MHC proteins are the same as the mother’s -- this is enough to prevent graft rejection. The outermost layer of the placenta does not express MHC molecules. She only tolerates it for 9 months, then she rejects it. Tolerating a fetus is good practice for tolerating a teenager later. No one knows. Clicker question Why did the immune system evolve to reject transplanted organs? 1) 2) 3) 4) To prevent animals from exchanging grafts in the wild. To frustrate transplantation surgeons. To force Bi1 students to learn about histocompatibility and MHC molecules. Because graft rejection is a by-product of an essential immune function. Zinkernagel & Doherty, 1974 Infect mouse with virus A. Isolate cytotoxic T lymphocytes (CTLs or “killer” T cells) from spleen of mouse X. Look for killing of virally-infected target cells derived from self (X) or non-self (Y) mouse. Killing + - CTL X X X Target X X Y Virus A B A See Bi1 website for link to Zinkernagel and Doherty’s 1996 Nobel prize for this experiment. Clicker question Which of the following scenarios explains Zinkernagel and Doherty’s data? 1) T cells have two types of receptor; one for antigen and the other for MHC. Both receptors must be occupied to get killing. 2) T cells have one type of receptor, which recognizes a complex between the MHC molecule and the antigen. 3) Both scenarios explain the data. 4) Neither scenario explains the data. Antibodies recognize free and cell-bound antigens independent of MHC proteins TCR recognizes a viral antigen and an MHC molecule, perhaps in a complex. One receptor, two receptors? Now understood that TCRs recognize antigen in the form of a peptide* bound to an MHC protein. Viral proteins are degraded into peptides inside cells and presented on class I MHC proteins for recognition by T cell receptors (TCRs) on cytotoxic T lymphocytes (CTLs or “killer” T cells). The receptors on B cells (antibodies) are made in both membrane and secreted forms. The receptors on T cells (TCRs) exist only as membrane-bound proteins. * Peptide: A short fragment of a protein. In general, a peptide is considered to be a protein if it is 50 amino acid residues. The peptides presented by class I MHC molecules are 7-10 residues. • Note that T cell mediated responses are restricted to CELLS, whereas antibodies can see soluble antigens (e.g., viruses). T cells can’t kill viruses, can only kill virallyinfected cells. • Viruses can mutate rapidly so can easily destroy antibody epitope, then virus can’t be neutralized. Mutated virus goes on to infect cells, but infected cells can be killed by T cells. Unlikely that virus can make all peptide sequences different to prevent binding to all MHC molecules. Class I MHC proteins Crystal structure of HLA-A2 • Peptide binding site identified as groove between 1 and 2 domain helices; allele-specific differences cluster in groove. • Groove was occupied by mixture of peptides although cells from which protein was purified were not expected to be presenting antigen. • Implies that MHC proteins always presenting peptides -why don’t T cells recognize MHC/self peptides and kill uninfected cells? Remember: Viral proteins are degraded inside cells and presented on class I MHC proteins for recognition by TCRs on cytotoxic T lymphocytes (CTLs or “killer” T cells). • MHC molecules are (almost) always occupied with peptides (usually self peptides, occasionally non-self peptides), so T cell has be able to distinguish. • Auto-immune diseases result from T cells that mistake a harmless self peptide for a dangerous non-self peptide. • Graft rejection results from a cross-reaction in which non-self MHC plus peptide Y (random self peptide) “looks like” self MHC plus peptide X (pathogenderived peptide). The receptors on T cells (TCRs) exist only as membrane-bound proteins. Variable residues located within peptide-binding site create different environments for binding different types of peptides Allele-specific peptide binding motifs Allele 1 Allele 2 Different class I MHC molecules bind to different types of peptides, but peptides that bind to every allele are (almost) always 7-10 residues long and usually have a hydrophobic C-terminus. Class I MHC-binding peptides can be predicted by computational analysis of protein sequences. See link on reading/links for today’s lecture on Bi1 website. Janeway et al., The Immune System in Health and Disease; Garland Publishing DR and Dw molecules are class II MHC proteins. Goldsby, Kindt, Osborne, Kuby. Immunology, 5th edition. Rusty, the narcoleptic dog < Review: The cellular immune response evolved to deal with viruses that mutate and hide out in cells • Many viruses, including HIV, rapidly mutate so that antibodies produced against one strain don’t react with new strains. • Another problem: once a virus enters a cell, antibodies can’t access it, so it can make thousands of copies of itself. • The cellular immune response (T cell mediated) can usually deal with both viral mutations and intracellular viruses. Comparison of antibody versus T cell epitopes on a model antigen shows how the antibody-mediated (humoral) and cellular immune responses are complementary Discontinuous epitopes (adjacent in 3D space, but not in sequence) on the surface of a protein are recognized by antibodies. Linear epitopes recognized by TCRs. Note red epitope is in interior of protein and only accessible after unfolding and proteolytic degradation. Easier for a viral protein to mutate to escape antibodies than to escape from T cells Janeway et al. (2001) Immunobiology: The immune system in health and disease. Garland Publishing, 5th edition Clicker question At what level is the polymorphism of MHC molecules a benefit? A) An individual has a variety of MHC proteins to present various antigens. B) A population infection. C) Both. not wiped out by a single viral ...
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This note was uploaded on 09/25/2010 for the course BIO 1 taught by Professor Bakorman during the Spring '09 term at Caltech.

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