BIOL 318 Immunology Lecture 4 PDF

BIOL 318 Immunology Lecture 4 Lecture by Andrea Verdugo Meza, PhD Candidate, MSc, BioEng Email: [email protected] September 16, 2024  Activity time (10 min) In groups, answer t...

BIOL 318 Immunology Lecture 4 Lecture by Andrea Verdugo Meza, PhD Candidate, MSc, BioEng Email: [email protected] September 16, 2024  Activity time (10 min) In groups, answer the following questions: 1. What represents the firs line of defense against pathogens? 2. Then, what is the second line of defense? 3. What are examples of cell responses from the innate immune system? 4. If we are talking about an extracellular pathogen, like E. coli, what would be the effector mechanism activated? Describe this in the context of the innate immune response. 5. Now, if we are talking about a intracellular pathogen, like a influenza virus, what would be the effector mechanism activated? Describe this in the context of the innate immune response.  Place the steps of inflammation in order from earliest event (occurs first) to the latest event (occurs last). Neutrophils and other immune cells begin to exit the A circulation and move into the tissues. Phagocytes and antibacterial substances destroy B bacteria at the site of damage. Macrophages at the site of damage are activated by C binding of PAMPs to their PRRs. Inflammatory mediators are released including D leukotrienes, prostaglandins, and histamine. How to enter: ABCD (do not use spaces or commas) © Macmillan Learning 2023  Place the steps of phagocytosis in order from earliest event (occurs first) to the latest event (occurs last). A Phagocyte engulfs pathogen, forming a phagosome. PRRs on phagocyte recognize and bind to PAMPs on B a pathogen. Pathogen is killed and digested inside the C phagolysosome. Pathogen breakdown products are released from the D phagocytes as waste. E Phagosome fuses with lysosome. How to enter: ABCDE (do not use spaces or commas) © Macmillan Learning 2023 Learning objectives To recognize the importance of the Major Histocompatibility Complex (MHC) for an effective immune response To describe antigen recognition in the context of MHC To describe antigen presentation in the context of MHC To understand MHC polymorphism and MHC restriction To contrast the role of MHC expression on cells of the innate and adaptive immune response Major Histocompatibility Complex (MHC) and expression patterns Major Histocompatibility Complex (MHC) proteins are molecules that serve as carriers of antigenic material Histocompatibility means “tissue compatibility” Two important MHC: MHC Class I and MHC class II MHC Class I is expressed on all nucleated cells MHC Class II is restricted to antigen-presenting cells 8  T cells respond to antigen only if the antigen is “presented” to them MHC proteins form a complex with fragments of antigens and then the T cell receptor (TCR) binds to the MHC- antigen complex Dendritic cells are a key bridge between the innate and adaptive immune response  MHC proteins form a complex with fragments of antigens and then the T cell receptor (TCR) binds to the MHC- antigen complex Dendritic cells are a key bridge between the innate and adaptive immune response The T cell receptor (TCR) recognizes a short peptide carried in the groove of a MHC protein on the surface of an Antigen-Presenting Cell (APC) T helper cell T cytotoxic cell recognize in the recognize in the context of MHC context of MHC class II class I MHC molecules present both intracellular and extracellular antigens Peptides from both self and non-self proteins Displays self-peptide to test developing T cells for auto reactivity and maintain tolerance Class I presents intracellular antigen peptides Provides a way for “checking” that cells are self and are generally healthy Can be used to show which cells have been infected with viruses or are abnormal Class II presents extracellular antigen peptides More restricted: found on cells involved in immune responses Helps to direct responses against threats―things that shouldn’t be in our systems 12  The structure and function of MHC molecules → Some amino acids anchor the peptide into the groove → Other amino acids extend from the groove and are available to interact with a TCR 13  The structure and function of MHC molecules MHC I MHC II Present antigens Present antigen to CD8+T cells peptides to CD4+T cells Peptides derived from endogenous Peptides derived intracellular from exogenous proteins extracellular processed antigens Highly conserved α3 domain binds CD8 Highly conserved α2 and β2 domains binds CD4 14 Antigen processing pathways The location of the pathogen dictates the type of response Virus in cytosol → MHC class I pathway → CTL Extracellular pathogen → MHC class II pathway → Th response → Ab production 15 MHC-I and -II exhibit polymorphism in the peptide-binding site The class I and II MHC genes are polymorphic Unlike most genetic loci that are monomorphic: >99% of the individuals in a species are genetically identical at that site Genetic Polymorphic = Different forms of a gene = multiple alleles MHC class I and II loci have >100 allelic variants in humans Co-allelic expression makes the whole species contain an enormous variety of combinations MHC proteins vary from individual to individual It is unlikely that any two individuals of an outbreeding species, like Homo sapiens, are identical for all the MHC proteins that cells express → except for monozygotic twins At the MHC, we are all different → barrier for tissue transplantation  MHC regions contain dozens of genes Class III MHC genes: complement and MHC locus inflammatory encodes three proteins major classes of molecules 17  MHC alleles are co-dominantly expressed Both maternal and paternal MHC genes are expressed in offspring cells Each individual inherits one haplotype from each parent Haplotype = group of genes inherited from each parent This gives the best chance for an organism to have some capability of presenting all the possible antigen peptides it encounters Mice breeding and transplantation to understand MHC self-restriction Syngeneic: identical at all genetic loci Inbreeding mice results in controlled variability for MHC genotypes Congenic: genetically identical except in a single genetic region Letters and numbers identify various MHC alleles The combination of possible alleles makes its haplotype, for example, bbbb The offspring carry one copy of each parental haplotype: A cross between C57BL/6 (b/b) and AKR (k/k) will produce mice (F1) that are bbbb/kkkk or H2b/k 19 MHC genes are codominant → both sets of genes are expressed That means each cell expresses both the maternal and paternal alleles of these genes and that the progeny of these crosses will accept transplants from either parent strain- either b or k haplotypes; they recognize both as self The parents will reject transplants from the offspring because they contain foreign=non-self MHC proteins. Class I/II molecules exhibit diversity at individual and species levels Individuals express MHC alleles inherited from both parents Heterozygous individuals express gene products encoded by alleles at each MHC gene locus Each parental chromosome’s MHC alleles are co- dominantly expressed in the offspring Because MHC-II are heterodimers, new molecules containing one maternal-derived and one paternal-derived chain are also produced Increased diversity MHC, why is so special? Polymorphism & self-restrictions  Important aspects of the MHC Alleles for MHC genes are co-dominant Each MHC gene product is expressed on the surface of an individual cell Each MHC has ONE peptide binding site But each MHC can bind many different peptides Only one at a time MHC polymorphism is determined in germ-line (from parents) There are no recombination mechanisms for creating diversity in MHC Peptide must bind with individual’s MHC to induce T-cell mediated responses 23 Why is MHC polymorphic? Let’s consider 2 scenarios: o All individuals have the same MHC o Each individual has a different MHC 24 Why is MHC polymorphic? Let’s consider 2 scenarios: o All individuals have the same MHC o Each individual has a different MHC Died Died Died Virus MHC Why is MHC polymorphic? Let’s consider 2 scenarios: o All individuals have the same MHC o Each individual has a different MHC Died Virus MHC 26 MHC polymorphism ensures that all individuals in a species are not equally susceptible to an infection o This is the reason why outbred populations are less susceptible to disease. o Cheetah: population bottleneck (of unknown cause) and subsequent inbreeding sometime in the past several thousand years. → All cheetahs now come from this small gene pool. o Human examples: marrying cousins  MHC haplotypes influence our mate choice? Studies in mice, fish, birds and humans reveal that mates are chosen based on a more diverse MHC haplotype Odor: MHC molecules are found in body fluids Urine of mice and men from distinct MHC congenic lines can be distinguished by other mice or men Mice will show a preference for mating with mice that carry MHC alleles that are dissimilar Humans prefer a sweaty T-shirt (measure of sexual attraction) worn by individuals that were later shown to be of a different MHC haplotype Peptide binding group  Resources from another immunology book that might help https://ubc.summon.serialssolutions.com/search?spellcheck=true&s.q=abbas+intr oduction+to+cellular+and+molecular+immunology#!/search?pn=1&ho=t&include.ft. matches=t&l=en&q=abbas%20introduction%20to%20cellular%20and%20molecula r%20immunology  MHC expression can change with changing conditions Genetic regulatory components: Promoters that drive up transcription during times of infection Viral interference: Viruses like to shut down MHC Class I expression because it targets the cells they’re in for destruction Cytokine-mediated signaling Some cytokines IFN-γ and TNF-α expressed first during infection/disease can drive up MHC expression whereas corticosteroids and prostaglandins downregulate MHC expression  Self-MHC restriction T cells recognize Ag in the context of MHC T cell antigen receptor binds to a complex of a self-MHC protein + Ag fragment Can T cells recognize Ag in any MHC? No T cells are restricted to recognizing the context of self-MHC only The MHC haplotype of the APC must match the haplotype of the T cell Ag recognition by Tc cells exhibit MHC restriction Zinkernagel and Doherty: 1. They immunized mice of one strain (H-2k) with Lymphocytic Choriomeningitis Virus (LCMV), 2. Then they waited a week and removed the spleen 3. Then they tested the ability of the spleen T cells to kill various target cells in a Cr51 release assay Results: T cells will kill and lyse infected cells that have the same MHC-I haplotype as the Tc cells presented with Ag. 33  Self-MHC restriction 1. Inbred guinea pigs from either of the two strains or the F1 of the cross were Ovalbumin-immunized 2. Then their lymph nodes were removed and T cells purified. 3. They mixed the T cells in culture with macrophages plus ovalbumin and measured the amount of T cell proliferation Results: T cells can proliferate only in response to Ag presented by macrophages with the same MHC-II alleles  Cross-presentation of exogenous antigens Dendritic cells appear to be the primary cross-presenting cell type Exogenous antigens are redirected to the endogenous presentation pathway This allows for their presentation on MHC class I molecules, priming CD8+ T-cell responses Dendritic cells are the only APCs (so far) to exhibit this activity in vivo Summary TCR-Ag-MHC in immune response Single T cell receptor binds to a combination of a peptide from a foreign protein and self-MHC The TCR must recognize both Ag and MHC: the receptor is specific for both partners in the compound determinant Understanding how intracellular and extracellular antigens are processed for presentation gives us insight into why different T cells are stimulated/ activated during immune responses 36