T and B cells Flashcards
Where do T and B cells develop
A Common lymphoid precursor goes to a generative lymphoid organs (primary or central lymphoid tissues), then the immature lymphocytes travel through to the blood and lymph, then mature lymphocytes go to peripheral lymphoid organs (lymph nodes, spleen, mucosal and cutaneous lymphoid tissues) and go back to the blood and lymph
B lymphocyte lineage–> bone marrow maturation
T lymphocyte lineage–> thymus
The Antigen receptors of B and T cells
Bind epitopes in a highly specific manner
Trigger response in the lymphocytes in which they are expressed
The Antigen receptors need to tell apart many different ligands that are really similar
The Antigen receptors are clonally distributed, the cells of each clone have a unique Ag receptor expressed many times on their surface
T and B cell antigen receptors bind chemically different epitopes
B cell receptors bind non-degraded antigens of many types (protiesn, lipids, carbs, nucleic acids)
Tcell receptors bind complexes of MHC molecules and peptides (degraded proteins)
The Ag receptors require additional components to which they are non-covalently linked to transmit signals to the interior of the cell, theses form the B cell receptor complex and the T cell receptor complex
The Ag receptors of lymphocytes are composed of variable domains that form the Ag binding site and constant domains that maintain overall structure
Immunoglobulins ma be membrane bound or secreted, t cell receptors are only ever membrane bound
Antibody Structure B cell antigen Receptor
There are 5 different classes (isotypes) that are functionally different due to constant region different Light chains are either kappa or lambda (does not change during class switching)
Each immunoglobulin variable region (heavy and light chain ) has 3 regions of hyper variablitliy
These are contact sites for the epitope in the Ag binding site
Isotype, allotype, vs idio types
Isotype-if an animal is immunized with human Ig, it will generate an antibody response to the non self protein, Antibodies directed against common epitopes on a given isotype will react with the same isotypes from any human. (ex: anti IgG atibodies will react with all human IgG molecules) (CONSTANT DOMAIN CHANGE)
Allotype: within the light and heacy chain constant regions there are a few polymorphic residues. Usually single amino acid interchanges. These also may serve as epitopes. Ab will present that will react specifically with the allelic variants (aka everyone has different IgGs) (DIFFERENCE BETWEEN SPECIES)
Idiotype- Epitopes associated with the variable regions of Abs are unique to a given Ab, Ag binding regions of antibody. (Ag BINDING DIFFERENCES IN VARIABLE REGION)
How is receptor diversity generated
REarrangement of genomic gene segments: of a large number of variable gene segments rearranges to pair with a J region segment
This construct
Properties of Antibody receptors and T cell antigen receptors
Antibody (immunoglobulin) receptor: recognizes Macromolecules (Proteins, polysaccharides, lipids, nucleic acids), small chemicals, conformational and linear epitopes
Each clone has a unique specificity, the Ag recognition is mediated the Variable (V) regions of the heavy and light chains of membrane Ig, signaling function is mediated by protiens (Igalpha and beta, associated with membrane Ig, effector functions are mediated by constant (C) regions of secreted Ig)- which could be complement fixation or phagocyte binding
T cell receptor (TCR): is recognized by Peptides displayed by MHC molecules on APC, typically small linear epitopes, each clone has a unique specificity (more diverse than B cell), Ag recognition is mediated by Variable regions of alpha and beta chains, signaling functions are mediated by proteins (CD3 and zeta), associated with TCR, the TCR DOES NOT perform effector functions
Features of the 5 major isotypes (classes of antibodies)
(Ig- A, D, E, G, and M), function is derived via the constant regions, recognition is derived from the variable regions, (FAB, CDR1 2 and 3)
IgG is the most abundant (also the smallest, a monomer), opsonization complement activation, ADCC, neonate, inhibitor of B cell
IgA- usually a dimer, mucosal immunity
Ig D- rarely found, transiently secreted for naive b cell Ag receptor
IgE- monomer, mast cell actication, hypersensitivity, helminth
IgM- pentamer, naive b cell Ag receptor, complement activation
Features of Ag recognition by Ab and T cell Antigen receptors
Immunoglobulin: Ag binding made up of 3 CDRs in heavy chaing and 3 CDRs in the light chain variable regions, The Ag thats bound is recognized via the linear and conformational determinants of macromolecules and small chemicals, affinity of Ag binding Ig increases dueing immune response, Rapid on rate, variable off rate, no accessory molceules involved in binding
T cell receptor, Ag binding made up of 3 CDRs in alpha and 3 CDRs in beta variable chains, only 1 to 3 AA residues of a peptide and polymorphic residues of an MHC molecule, no change of afffinity during an immune response, slow on rate, slow off rate, acessory molecules involved in binding (CD4 or CD8 simultaneously binds MHC
Sequence of Ig and TCR Gene rearrangement events
Common to both Immunoglobulins and the T cell antigen receptor
- The VARIABLE region of the Ig heavy chain/ TCR beta chain is composed of 3 gene segments that combine during different cellular differentiation and maturation. These segments are V, D and J. The 1st recombination event is the heavy chain D and J followed by recombination of V with DJ. VDJ then recombines with a CONSTANT region gene segment. The heavy chain transcript (VDJC) is then processed and expressed with in the cell
- the Ig light chain/ TCR alpha chain V and J then recombine, and the VJ recombines with a C segment to form a transcript for the light chain. This is translated and expressed in combo with the heavy chain to form the intact protein, which is expressed on the cell surface
- These somatic gene recombination processes are mediated by an enzyme complex made up of Rag 1 and Rag 2 proteins
Mechanism of diversity in Antigen receptors
not only due to rearrangement of VDJ and VJ: Combinatorial diversity (aka rearrangement) and Junctional diversity (aka special proteases cleave and addition join of nucleotides)
Mix and match pairing of light and heavy chians
Somatic hypermutation (Ig affinity maturation), doesnt change variable region, just increases affinity
Allelic exclusion
We get one chromosome from our mom and one from our dad, a process allows for onyl one version of the receptor to be present
For an Ig or TCR chain to be expressed, all recombination must be in the proper reading frame
If the first Ig heavy chain recombination even occurs on the maternal chromosome and is successful, the heavy chain genes on the paternal chromosome will not reattange and the cell will only express moms gene product, if neither mom or dad is successful the cell dies, expression is random
This process ensures clonal specificity
RAG is the main player (autosomal SCID)
Steps in the maturation of the lymphocytes
Pro B/T cell is subjected to IL7, alloing them to proliferate
Pro B/T cell needs to express a pre lymphocyte receptor (failure to do so leads to cell death)
Pre B/T cell expresses one chain on Ag receptor (failure to do so leads to cell death)
Immature b/T cell expresses the complete Ag receptor (then subject to positive and negative selection)- need s a weak self Ag recognition, a strong– neg selection, an absent–failure of postitive selection
Steps in the maturation and selection of B lymphocytes
Stem cell–> pro B cell subject to IL 7 –>Pre B cell (expresses m chain)–> Immature B cell expresses IgM–> Mature B cell thats naive expresses Ig M and Ig D–> travels to peripheral lymphoid tissues, Ag activates BCR–> Activated B cells undergo isotype switching to secrete Antibodies
B cell interaction with self molecules
Since rearrangment of the Ag receptor is random, receptors reactive with self molecules may be present,
B cells with auto reactive receptors must be removed or functionally inactivated in a process called negative selection
T cell matureation and selection occurs in the thymus
- postitive selection in cortex of thymus
- negative selection in medulla
a few self reactive T cells escape the system, and will be kept in check via Treg cells
