Lecture 8: Adaptive Immunity 1.

T-cells arise from lymphoid progenitors in the bone marrow then migrate to the thymus where it undergoes development, differentiation, and maturation. a. Key is formation of the T-Cell receptor (TCR) complex and other surface proteins that recognize antigen fragments. i. These fragments are only recognized when presented by a Class I or Class II MHC molecule. b. Molecules outside the TCR are acquired to define function of T-cell. 2. T-Cell Receptor (TCR) makeup a. Composed of two transmembrane polypeptide chains i. Either alpha/beta or gamma/delta 1. Alpha/Beta is the best defined b. Expressed in association with CD3 i. Links antigen binding receptor with T-cell pathway intracellularly. Cellular cascade once bound. 3. Alpha and Beta chain makeup in the TCR a. Made up of a variable and constant region b. TCR alpha is equivalent to light chains in B-cells i. Made up of a V and J segments c. TCR beta is equivalent to the heavy chains in B-cells i. Made up of V, D, and J segments 4. T-Cell Development (in the Thymic Cortex) a. Cell surface expression of T-Cell molecules i. CD2 is the first molecule present 1. CD2 is the pan T-cell marker* ii. Also expressed is Pre-TCR-CD3 complexes, CD4, CD8, and TCRCD3 complex. b. The cells are initially double positive T-cells i. This means that they are both CD4 and CD8 c. Somatic recombination i. Like B-cells Pre-TCRs undergoes this to create unique variable regions. 1. As in B-cells this is initiated by RAG-1 and RAG-2. ii. Leads to creation of the T-cell repertoire d. Allelic exclusion. i. Occurs following somatic recombination ii. In this process somatic recombination of the other member of the chromosome is inhibited following successful rearrangement of a TCR variable chain region. 1. Remember there are two possible chromosomes; once one is used successfully the other is inhibited. e. Tolerance induction i. A process that eventually destroys or inactivates autoreactive T-cells.

1. Paradoxically first the cells are selected by if they do recognize the self-MHC. 2. Next they are destroyed via negative selection or Death by neglect. a. Negative selection occurs when the avidity of the T-cell exceeds a pre-determined recognition threshold. b. Death by Neglect occurs when the avidity of the T-cell is insignificant. 3. If cells are desired they are selected through positive selection, which expands the T-cell. a. Positive selection cells have avidity that is intermediate. ii. What is avidity again? 1. It is how well the receptor interacts with its antigen. a. In the case of T-cells it is the reaction between Tcells and self-antigen/MHC. 2. What determines it? a. Intrinsic affinity of TCR for self-antigen/MHC b. Density of TCRs c. Density of self-antigen/MHC d. Density of antagonistic peptide complexes i. Interactions that repel one another f. Lineage selection i. Earlier we mentioned that T-cells were double positive during development, i.e. they were CD4 and CD8. ii. In this process T-cells become exclusively CD4 or CD8. 5. T-Cell Development (in the Thymic Medulla) a. Negative selection also occurs here b. More importantly the T-cells are exposed to the AIRE protein, aka Autoimmune regulator protein. c. AIREs job is to present proteins found exclusively in other tissues of the body. As a result the body can judge whether or not the T-cells are going to react in various locations of the body. i. The Holodeck of the body if you will. ii. If the cells avidity for the self-antigen/MHC is too high it is destroyed. 6. What types of cells leave the Thymus? a. Three kinds i. CD4+Thp 1. T-helper cells ii. CD8+pCTL 1. Cytotoxic T lymphocytes iii. CD4+/CD25+/FOXP3+ 1. nTregs 7. nTregs (CD4+, CD25+, FOXP3+)

a. Special kind of cells that are NOT destroyed when their avidity for the self-antigen/MHC is high. b. The job of these cells is to control self-reactive T-cells. i. Low numbers predispose us to autoimmune and inflammatory disorders. ii. An interesting concept is that if you have low levels of nTregs you also will have a stronger immune response. This is because T-cells are not kept in check and react more strongly than if they were regulated. 8. T-cell trafficking and migration a. When lymphocytes leave their maturation sites they either seed secondary lymphoid tissue or circulate in immunosurveillance. b. Migration into lymph nodes occur at specialized HEV when antigen is detected (This also occurs at other site when antigen is present). Takes place into four steps. i. Lymphocyte rolling 1. L-selectin causes this 2. Makes the lymphocyte slow down and stick to the wall while going by the antigen site ii. Integrins 1. For example LFA-1 2. Increases adhesiveness and allows for stable binding a. The lymphocyte stops rolling and moves in iii. Matrix Metalloproetinases 1. Degrade collagen to give lymphocytes a pathway in iv. Transendothelial migration of lymphocytes into the tissue 1. Lymphocytes move into the tissue.