PCB 3233 Exam 3 Study Guide Chapter 5 1 BCRs are created in bone marrow undergo somatic recombination and migrate to secondary lymphoid tissue TCRs mature in the thymus and also undergo somatic recombination 2 An immunoglobulin consists of a heavy chain variable and 3 or 4 constant domains and a light chain either kappa or lambda A TCR consists of an alpha and a beta chain each with 1 variable domain and 1 constant domain 3 A TCR will recognize antigen peptide together with a MHC molecule A BCR will recognize a specific antigen without it being presented by another cell A BCR will recognize lipids carbohydrates and proteins whereas TCRs will only recognize protein 4 A TCR will have 2 epsilon 1 gamma and 1 delta chain CD3 complex along with 2 zeta chains All of these are used for intracellular signaling to the nucleus Lack of functional delta and epsilon chains results in immunodeficiency 5 The function of a TCR is to recognize peptide being presented to it on a MHC molecule and then secrete cytotoxins to induce apoptosis or cytokines to activate a macrophage or B cell 6 The CD3 complex consists of 2 epsilon chains 1 gamma chain and 1 delta chain These proteins are used for intracellular signaling 7 The TCR FAB is composed of the variable regions of the alpha and beta chain each with 3 CDRs so one TCR has 6 CDRs TCR diversity is dependent on variable region gene rearrangement and junctional diversity Most variability is clustered into the CDR regions and more specifically the CDR 3 region After activation T cell does not undergo somatic hypermutation or isotype switching 8 Severe combined immunodeficiency syndrome one of the RAG genes is not functional so no functional T or B cells infant usually dies very early on Omenn syndrome is due to a RAG protein with partial enzymatic activity causes red rash on shoulders and face Bare lymphocyte syndrome is due to a non functional TAP protein so no MHC I is present on surface of cells which results in poor responses to viruses Heterozygosity of the HLA class 1 and 2 loci results in HIV taking a longer time to progress to AIDS 9 The delta gene segment is located in between V and J regions of the alpha chain If the V and J regions are rearranged the delta gene segment is cut out The gamma gene segment is located on chromosome 7 The delta and gamma chains have fewer V segments but the delta chain makes up for this by rearranging up to 2 D gene segments which results in more junctional diversity as well Typically delta gamma TCRs have much less diversity but have potential for more 10 Delta gamma TCRs 1 5 of all TCRs do not need antigen presented to them by MHC molecules the delta chain can rearrange two D segments and they can be dominant in the epithelial tissue 11 MHC class 1 molecules present intracellular peptide whereas MHC class 2 presents extracellular peptide Class 1 molecules present to CD8 cytotoxic cells and class 2 molecules present to TH1 and TH2 cells Nearly every nucleated cell expresses MHC 1 molecules but MHC class 2 are mainly expressed by dendritic cells macrophages and B cells sometimes thymic epithelial cells MHC class II molecules can be produced by other cell types on exposure to the cytokine interferon g 12 MHC class 1 consists of 3 alpha domains and beta 2 microglobulin not encoded by MHC genes Alpha 1 and 2 form the binding site and alpha 3 and beta 2 microglobulin form the supporting structure MHC class 2 consists of an alpha chain and a beta chain Alpha 1 and Beta 1 form the binding site and Alpha 2 and Beta 2 form the supporting structure Supporting structure proteins also form binding sites for the CD4 and CD8 co receptors alpha 3 on MHC 1 and beta 2 on MHC 2 13 MHC class 1 molecules can bind peptides 8 10 amino acids long which are pinned down at the ends of the structure MHC class 2 can bind peptides 13 25 amino acids long because peptides are pinned along the groove of the binding site and extend through the ends of the binding site 14 MHC molecules bind peptide non covalently In MHC class 2 peptide may extend to outside of the groove The binding groove is made up of 8 antiparallel beta sheets and 2 antiparallel alpha helices The peptide lies between the 2 alpha helices and parallel to them 15 The promiscuity of MHC molecules allows for 1 MHC molecule to bind to up to 10 000 different antigens 16 Intracellular pathogens are broken down and presented on MHC class 1 molecules to CD8 T cells Extracellular pathogens are endocytosed degraded and presented on MHC class 2 molecules to either TH1 T cells which activate macrophages or TH2 T cells which activate B cells 17 See 16 18 Cytotoxic T cells leave the secondary lymphoid tissue and migrate to site of infection 19 MHC class 1 proteasome breaks down peptide TAP 1 and 2 transports peptide into endoplasmic reticulum Calnexin Calcium dependent stabilizes MHC class 1 until B2 microglobulin is made calreticulin and tapasin position MHC and helps load the peptide Once a peptide is loaded the molecule is exported to the cell surface MHC class 2 peptide vesicles travel inwards acidification of vesicles by a proton pump to make the enzymes functional fuses with lysosomes to form phagolysosomes which degrade peptide peptides bind to MHC class 2 which are exported to the cell surface 20 Proteasome degrades peptide for MHC class 1 TAP 1 and 2 transport peptides into the ER via hydrolysis of ATP Calnexin calcium dependent chaperone that stabilizes MHC 1 until B2 microglobulin is made Invariant chain blocks peptides from binding to MHC 2 in ER and delivers class II molecules to endocytic vesicles called MHC class II compartments or MIIC HLA DM catalyzes the release of CLIP CLIP small fragment of the invariant chain left to block peptide binding Chaperone molecules proteins that assist in correct folding of proteins and assembly of other proteins protection until they enter their respective cellular pathways and to carry out their intended functions 21 MHC genetic complex MHC class 1 and 2 are closely linked highly polymorphic alleles are co expressed B2 microglobulin and invariant chain not encoded here HLA A B and C have many different allotypes and present to CD8 cells HLA P Q and R present to CD4 cells HLA E and G present to NK cells 2 HLA DR B alleles can be inherited MHC gene region 3 doesn t encode for MHC molecules but for other immune functions 22 MHC class 1 and 2 get diversity through polymorphism The greatest diversities among the MHC molecules is in the beta