4/23/18. T cell receptor: V/D/J segments. Antibodies and T-cell receptors have a similar structure

Transcription

1 ntibodies and -cell receptors have a similar structure he -cell receptor resembles a membrane-associated ab fragment of immunoglobulin. cell receptor: //J segments

2 -cell receptor diversity is generated by gene rearrangement volution of reflects the evolution of adaptive immunity ()J recombination arose abruptly during early vertebrate evolution hompson et al. (), mmunity :- defect in ()J recombination results in severe immunodefiency hat do you think happens to an individual who lacks? = evere combined immunodeficiency syndrome absence of adaptive immunity ay be caused by mutations in at least different genes, e.g. the genes. fatal in the first years of life because of opportunistic infections herapy only possible if diagnosis is made at birth or shortly thereafter. herapy in the form of bone marrow stem-cell transplantation Buckley () mmunol es. (-):-

3 he magnitude of potential B and cell receptor diversity he magnitude of potential B and cell receptor diversity omatic recombination results in combinatorial & junctional diversity ecombination process generates diversity regions on igure courtesy of r. Hewit

4 β analysis of specific -cells against different viruses β () Jβ % H H H oning, et al J cell responses against different viruses he composition of the cell receptor complex cells function by interacting with other cells xpression of the cell receptor on the cell surface requires association with additional proteins

5 H class presents peptide antigens to cells H class presents peptide antigens to cells H = major histocompatibility complex tructure of H class and class are similar! H molecules bind a variety of peptides rocessing of antigens which bind to H class or occurs in different cellular compartments rocessing of antigens which bind to H class or occurs in different cellular compartments

6 H class binds peptides as part of a peptide-loading complex n infected tissue, cells switch to immunoproteasome for protein degradation refential cleavage after hydrophobic or basic residues produces peptides that fit the terminal binding motif of and many H allotypes. lein et al. (), at ev mmunol ():- n the, peptides may be further trimmed from the -terminal end by an amino peptidase he H class antigen processing pathway H class molecules are prevented from binding peptides in the endoplasmic reticulum by the invariant chain = class -associated invariant-chain peptide

7 ross-presentation by dendritic cells ifferential expression of H class and molecules professional antigenpresenting cells { yas et al. () at ev mm. :- he major histocompatibility complex iversity of H class molecules in human population is caused by polymorphism luster of closely linked genes on chromosome umerous genetic variants of H class and present in the human population => diversity due to multigene families and genetic polymorphism he human H: human leukocyte antigen (H) complex

8 How many H molecules do we find in the human population? # of rotein sequences (/H database) hat are the functional differences between different H molecules? H- H-B H- H polymorphism affects the binding and presentation of peptide antigens to cells eptide binding motifs of some H class and allotypes he most polymorphic amino acid residues map to the peptide binding site. anchor residues * B*

9 great variety of binding motifs H B* * H * * * * and * have very different peptide binding motifs. B* B* * eemingly small differences may have a big impact on the peptide binding motif! cell recognition of antigens is H restricted obel rize edicine But: ome cells are alloreactive => problem for organ and bone marrow transplantations!

10 H molecules are expressed in a codominant fashion. H molecules are expressed in a codominant fashion. hich consequences does that have for an individual? hich consequences does that have for an individual? Heterozygous individuals are able to present a more diverse set of peptides to their cells H heterozygosity delays the progression to orldwide H class diversity: Balancing selection raction of H- infected individuals who remain -free ears since seroconversion arrington et al. cience ;:- oulder & atkins () at ev mm. :-