Immunology: T cell development and Selection

Precursor T cell can go αβ, OR γδ TCR route

-Double negative T cells start to rearrange β, γ, and δ loci 1.γ and δ genes rearrange,γδ receptor assembles, stops further rearrangements > Matures into γδ cell 2. β rearranges, pre TCR assembles, signals through pre TCR stop rearrangment, induce expression of CD4 CD8, then cell rearrangement continues??

Describe the structure of the thymus

-STROMA of epithelial cells and CT -provides microenvironment of T cell development and selection -lobules split into outer cortex and inner medulla, filled with thymocytes form bone marrow -dendritic cells present

Peripheral tolerance

-T regulatory cells and regulatory receptors help tamp down T response when it gets too crazy and strong

T cell receptor: structure

-TWO chain heterodimer (α and β, OR γ and δ) -variable region, constant region, transmembrane region -CD3 help transport the signal

Genetic basis of TcR antigen-recognition diversity

-VJ and C regions rearrange like in the B cell and meet with different VJC regions (like α and β) -RAG enzymes randomly cut and recombine V,D,J -joints with N and P nucleotides

What are the CDRs?

-each TcR chain has 3 CDR's in variable region -hypervariable or complementarity determining region VARIABLE region actually contacts MHC

γδ T-cell

-emerge in waves during embryonic development -migrate to GI, pulmonary, and reproductive epithelium -response MUCH MORE rapidly than αβ (INNATE like) -bind to self MHC and MHC like molecules (like CD1 which recognizes lipids), recognize non protein antigens from important microbial patterns!!!!!

Autoimmunity implications

-if MHC making so many TCRs, then it is likely some will be matching to a self protein , lead to immune response against host

Auto immune regulator (AIRE)

-induces expression randomly by jumping around on genes and turning things on -epithelium can express things outside of thymus so exposure occurs

Central tolerance

-removal of self reactive T and B cells during development -T cell tolerance much more important than B cell tolerance since T cell needed to activate b cells

Self reactive T cells

-some antigens not present in thymus even with AIRE -some self peptides fail to form stable complexes on thymic stromal cells -failure of TcR to bind self peptide/MHC in thymus with sufficient avidity

What part of TcR actually reacts with peptide and self MHC?

-the variable region is what touches the MHC and the peptide

The Thymus

-where T cells undergo education -darker parts are rick in nuclei -atrophies with age

Cortex vs medulla of thymus

>Thymocytes, cortical epithelial cells, dendritic cells >Macrophage (eat up dead cells), medullary epithelial cell

Two classes of T cell receptors

>α chain and β chain , OR γ chain and δ chain

TcR development

HSC > Common lymphoid progenitor> migration from blood into thymus > T cell precursor > (double negative) DN1 (expressing certain factors) > DN2 > DN3 OR can change into γ δ cell > DN4 > Double positive (DP) > CD8+ or CD4+ then migrate out into periphery -90% alpha beta!

What determines αβ, OR γδ TCR ?

IF β rearranges first, it is αβ cell IF γδ rearranges, then γδ cell!

Do all T cells that mature in thymus come out?

No most die there -98% of them die without inflammation or change in size -thymic macrophages phagocytose apoptotic thymocytes

How does the T cell know if it will react with CD4 or CD8? Instructive model (in thymus)

Right now T cell is double positive! >If T cell receptor recognizes MHC class II, the CD4 its expressing will send signal (lose CD8) >if recognizes Class I, CD8 will saddle up to saddle chain, recognize it and signal T cell (lose CD4) Single positive thymocyte made

Negative selection

eliminate T cells that bind self MHC too tightly

Positive selection

reward T cells expressing TcR which can bind to self MHC

γδ T-cell go home to

specific epithelial tissues

Why do most cells die in thymus?

they are too useless or too dangerous >if too strong, leads to autoimmunity

Thymic atrophy

with age -however, still reasonably normal T cell bank when you are old

some autoimmune disorders

• TIDM • MS • Crohn's disease • Vitiligo • Rheumatoid arthritis • Hashimoto's disease