Introduction Lymphocyte development is complex and has several features including localization to primary lymphoid organs such as the bone marrow for B-cell development the thymus for T-cell development VDJ recombination in order to rearrange genetic material generate a unique B- or T-cell receptor positive selection in order to ensure all cells have functional receptors proliferation in order to expand the pool of potential lymphocytes allow for broad protection against different types of antigens negative selection in order to remove cells that target self-antigens protect against autoimmunity There are many mechanisms to increase diversity during lymphocyte development such as random recombination of genetic material during VDJ recombination random nucleotide addition to hypervariable regions by the protein TdT random assortment of different chains in receptor assembly heavy chains with light chains in B-cells alpha chains with beta chains in T-cells somatic hypermuation after antigen exposure only occurs in B-cells B-Cell Development B-cells develop in the bone marrow develop a unique B-cell receptor are tested to ensure that the receptor is functional are further tested for self-reactivity to prevent autoimmunity This development cycle is coordinated by the orderly progression through stages where supporting cells give feedback at every stage interaction strength of the B-cell receptor is monitored Stages of B-Cell Development Cell Type Development Steps Surface Receptor Associations Lymphoid stem cell Commitment to B-cell lineage None Pleuripotent Pro B-cell Heavy chain VDJ recombination Additional diversity from TdT modification Heavy chain only Recombination mediated by RAG proteins Defect in RAG leads toOmenn syndrome with no mature B cells Pre B-cell Allelic exclusion to ensure only one heavy chain expressed Positive selection Proliferation Pre B-cell receptor Key step in monitoring activity of the recombined heavy chain Immature B-cell Light chain VJ recombination Negative selection IgM receptor Inactivation of recombination machinery Key step in tolerance Mature B-cell Exit into blood stream IgM receptor IgD receptor Circulates and awaits activation by antigen T-Cell Development T-cells migrate from the bone marrow to the thymus where they develop a unique T-cell receptor are tested to ensure that the receptor is functional are further tested for self-reactivity to prevent autoimmunity This development cycle is coordinated by the orderly progression through stages where supporting cells give feedback at every stage receptors that bind too strongly lead to developing T-cell death the T-cell receptor undergoes selection in distinct compartments Stages of T-Cell DevelopmentCell TypeDevelopmental StepsSurface ProteinsAssociationsT-cell precursorCommitment to T-cell lineageMigration to thymusNoneLack of thymic development inDiGeorge syndromeDouble negativeRearrangement of the β T-cell receptor chainProliferationPre T-cell receptorOccurs in the thymic cortexDouble positiveRearrangement of the α T-cell receptor chainExpression of both CD4 and CD8Positive selection against both class I and class II MHCCD4CD8T-cell receptorOccurs in the thymic cortexKey step in determining type of T-cell that developsMHC II binding leads to CD4+ cellsMHC I binding leds to CD8+ cellsSingle positive Migration to medulla of thymusNegative selection against self antigensT-cell receptorEither CD4 or CD8The transcription factorAIRE allows medullary cells to express proteins from all areas of bodyThis ensure tolerance to vast majority of self antigensMature T-cellExit into blood streamAwaits peripheral activationT-cell receptorEither CD4 or CD8Circulates and awaits activation by antigen